A giant sinkhole opens up in the middle of Seattle, where Callie, Owen, and Alex are sent to help the first responders. April is struggling to settle into her place as Chief Resident, finding it difficult to persuade her fellow residents to respect her position. Cristina and Owen are not speaking to each other, as they do not see eye-to-eye on what to do about Cristina's unplanned pregnancy. In response to Meredith's actions at the end of last season, the hospital board decides that Meredith should be fired as a resident at Seattle Grace Mercy West Hospital. The loss of her job only adds more strain to Meredith and Derek's already precarious relationship, as well as increasing complications to their current attempt at adopting Zola. Social Services realizes that Meredith has been fired and that she and Derek are not currently living together, causing Meredith to panic. The episode closes with Meredith taking Zola from daycare, seemingly taking her away from the Hospital without permission.

The sinkhole crisis continues, with the patients that the surgeons helped rescue now within the Hospital. Dr. Bailey and the other attendings give the residents a patient that they must all work together to save, in order to see which resident will come out as a leader. Cristina makes a decision regarding her unplanned pregnancy, and Owen goes with her to her abortion. Social Services and Derek spend the day searching for Meredith and Zola, and when Cristina finds Meredith hiding in the hospital she enlists Alex to pretend that he has been seeing Zola as a patient all day. Richard goes to the hospital board and lies to them, telling them that Meredith only destroyed Derek's clinical trial under his own orders. Because of this, Meredith is able to keep her job.

Dr. Webber announces that he is resigning as Chief of Surgery, and that Dr. Hunt will be replacing him as chief. April continues to struggle to gain respect from the residents while in her role as Chief Resident. The 5th year residents are given their first solo surgeries. Cristina and Owen try to find normalcy in their relationship after her unplanned pregnancy. They spend the episode attempting to awkwardly engage, and their relationship only goes back to normal after they get food poisoning together. Derek, still very angry at Meredith, tells her that while he will not walk away from their relationship, he cannot trust her at work. In response to this, Meredith decides she will no longer pursue neurosurgery, and they agree that if they want to fix their relationship and have a chance of adopting Zola they cannot work together.

Absent: Chyler Leigh as Lexie Grey due to family leave

Ben returns and Miranda is skeptical of his arrival, until Ben realizes that she has finally moved on. A stampede at a comic convention causes the ER to be inundated with colorful costume-bearers. This episode centers largely on the men of Seattle Grace as opposed to focusing on the women.

Jackson's mother, Dr. Catherine Avery, comes to Seattle Grace for a groundbreaking transplant surgery. Zola comes into the hospital. Alex and Arizona must deal with the confidentiality issue with Derek and Meredith. Teddy throws a house warming party. Eli and Miranda break up.

April steps up as Chief Resident while managing a clinical trial. Callie and Cristina deal with a difficult spinal surgery while Alex and Teddy must find alternative ways to operate on a patient. Meredith struggles to follow her new rule of not talking to Derek about work while at the hospital.

In order to stress cooperation and teamwork, Owen enters the doctors into a softball league where they will compete against Seattle Presbyterian, the other hospital in Seattle. Derek and Lexie deliberate a treatment plan when a desperate mother of a girl with an inoperable brain tumor specifically seeks his help. Richard tries to repair Miranda and Meredith's working relationship. Lexie becomes jealous over Mark dating a new woman, and Alex fights to keep Zola at Seattle Grace.

A medical miracle occurs, leaving the residents feeling inspired. Louise O'Malley returns to Seattle Grace after a surgery was botched by a different hospital, causing the residents to reminisce about all the times they had with George. Arizona makes friends with a new pediatric fellow, making Alex feel threatened. Teddy and Henry fight over Henry wanting to attend medical school.

Teddy brings Henry into the ER after finding him at home vomiting blood; while Meredith gets news from Janet that she and Derek aren't going to get Zola back. Just as Teddy waits on Henry's CT she is called onto another case, the case being Callie and Jackson's spinal surgery, whose heart is now bleeding uncontrollably. After deciding to operate on Callie's patient, Teddy decides to get Cristina to operate on Henry, with Dr. Webber and Lexie in with her, only not to tell her that it's him. Meredith and Alex go to a neighboring hospital to help a new premature baby, since the hospital doesn't have the equipment to save the baby's life; After believing that Henry is in the clear, Cristina finds that the tumor had gone into the heart; after twenty minutes of performing CPR Cristina calls time of death, only moments later to find out it was Henry. After their ambulance breaks down, Alex and Meredith call Arizona, Mark, and Derek to see if they knew how to take care of the baby, only for the ambulance to crash while on the phone; When Meredith and Alex step out, they see that a car with victims in it was what hit them.

The ER is swamped by victims from the crash which involved a family car and Alex and Meredith's ambulance. Alex and Meredith fight to save the lives of a family; after realizing that telling Teddy about Henry's death would stop her from saving her patient's life, Owen decides to not tell Teddy until she is out of surgery. When Meredith and Alex get back to the hospital they try to save the family's life, only for all but the father and the children of the family to die immediately. While operating on the youngest child of the family, Derek and Mark realize that they need help if they are going to save the child's eye, only to call Mark's ophthalmologist girlfriend, Julia, in to assist them, with Lexie assisting Derek. Arizona and Alex work to save the life of the baby that they brought from the hospital. Cristina struggles whether or not to tell Teddy about Henry in the middle of a critical surgery. At the end of the episode, Meredith and Derek get full custody of Zola back.

A risky surgery which involves conjoined twins has the doctors split into two teams. Meredith unwittingly finds herself acting as a buffer between Miranda and Ben, Alex is taught a lesson in the O.R. by Webber, and Teddy makes everyone in her O.R. uncomfortable when she has Cristina recount the events leading up to Henry's death. Back at home, Derek and Meredith find joy in parenthood.

A pair of bickering sisters come in for a liver transplant performed by Richard, making it his 10,000th surgery. Meredith must choose a new specialty, Derek and Lexie operate on a previously inoperable neuroblastoma, and Teddy and Cristina defy Owen and steal a case from Alex. Adele is brought to Seattle Grace after being found wandering the streets. She is brought to the OR gallery to see Richard performing his milestone surgery where an emotionally taxing moment occurs revealing the full extent of her Alzheimer's.

Meredith dreams of an alternative universe in which her mother, Ellis Grey, never had Alzheimer's and is a more supportive and loving mother. This leads Meredith to be a happy version of herself, causing Seattle Grace to be completely different. She and Cristina are enemies while April is her best friend, who is sleeping with Meredith's fiancé, Alex, who is only with Meredith because of her family's legacy. Owen has married Callie and they have 3 children, although they are not happy. Addison and Derek are expecting a child, only it is revealed that the baby is actually Mark's, and Addison and Derek's relationship is falling apart just as Derek's own career is also stagnating. Lexie has become an orphan and a drug addict. It is revealed that George failed his boards and was never seen again while Meredith turned Izzie in to her mother for her relationship with a patient, alluding to Denny (Jeffrey Dean Morgan), firing her. Richard left Adele and married Ellis, and Meredith took Webber as her last name. The episode ends reminiscent of how Derek and Meredith first met. Throughout the entire episode all the couples that actually do exist seem to have connections, which includes Callie and Arizona, and also Yang and Owen.

Absent: Kim Raver as Teddy Altman

It's Valentine's Day at Seattle Grace and the ER fills with romantics. The singles, Lexie and Mark, are stuck on babysitting duty. Miranda and Ben's plans are ruined when she is called away to a series of emergencies but Ben surprises her at the end of the day. Meanwhile, Owen and Cristina keep avoiding each other after their big fight.

During marriage counselling sessions, Owen and Cristina are constantly engaging in heated arguments. Owen cannot seem to move past the fact that Cristina does not want kids. Amelia arrives at Seattle Grace hoping to convince Derek to assist her with Erica's (A.J. Langer) gliosarcoma. Lexie gets caught in between the two Shepherds, Meredith shows off her surgical skills, Alex learns the importance of people skills, Mark and Jackson teach Dr. Bailey a lesson, and the residents continue to prep for their oral boards.

This episode begins a crossover with Private Practice that concludes on "You Break My Heart".

A coffee shop explodes, flooding the ER with patients. Richard reassesses his living situation with Adele as she continues to deteriorate before his very eyes. Callie assists Meredith with studying for her boards, Lexie assists on a peds case with Arizona and Alex, and Mark encourages Jackson to relieve his stress. Meanwhile, Cristina's suspicions get the better of her as she thinks Owen is cheating on her with a nurse.

Derek encourages a hesitant Meredith to work with him again in neurosurgery, but the results are less than ideal; Jackson’s mother, Catherine Avery, returns to Seattle Grace with a urology fellow and develops an interest in Richard; and Cristina becomes increasingly suspicious of Owen’s every move. Meanwhile, Alex tries to deny everyone's observations that Morgan may be falling for him.

A lion breaks loose in Seattle and leaves a trail of victims in its midst; Lexie overhears Mark's discussion about moving in with Julia; Teddy begins to take steps towards coming to terms with Henry's death; Callie grills Arizona on her past lovers; and Alex requests to be taken off Morgan's preemie case when she becomes too dependent on him. Meanwhile, Meredith tries to be a support for Cristina as the tension between her and Owen hits a boiling point after Owen cheats on Cristina.

Cristina and Owen call in sick to work out their marriage at home, but in the end Owen moves out. Mark takes his appointment as interim chief very seriously, much to the attendings' annoyance. Arizona, Callie and Miranda plan a special night for Teddy.

The doctors work on a Jane Doe, who turns out to be the subject of a case that gained national interest. Cristina proves to be in highest demand as the residents begin their interviews for post-residency positions at prospective hospitals while the attendings find ways to keep their best residents in Seattle. Richard is faced with an unsettling realization when he visits Adele at Rose Ridge.

The residents travel to San Francisco for the oral boards. Sparks fly when Richard and Catherine (Debbie Allen) bump into each other at a hotel. Alex feels guilty about being away from the hospital as Tommy's health takes a turn for the worse. April loses her virginity to Jackson.

The residents agonize over their upcoming exam results. Arizona's childhood friend needs medical help. The doctors try to help a patient who is missing one third of his skull. Julia wants to start a family with Mark, causing Lexie to finally tell him how she feels.

The 5th years make their final decisions regarding their post residency plans. Mark confides in Derek about being torn between Lexie and Julia. Arizona encourages a childhood friend to have surgery, and Ben plans something for Miranda, who is preoccupied with work. Meredith, Derek, Cristina, Mark, Lexie and Alex are scheduled to fly to assist in a surgery at a hospital in Boise, though Arizona takes Alex's place after she discovers he is planning to leave Seattle Grace for Johns Hopkins Hospital. However, en route their plane crashes in the woods, leaving their fates unknown.

Meredith, Derek, Cristina, Lexie, Mark, and Arizona are in a plane crash in the middle of the woods. They discover that Lexie has had her lower abdomen and legs crushed under part of the plane, and she dies shortly after due to her injuries. Derek was blown away from the scene of the crash, and he wakes up to find his hand trapped in a piece of metal pinning him to the ground. In order to get up to find the others in the crash, he breaks his hand with a rock so he can remove it from the metal. Arizona suffers a severe injury to her leg, and the pilot of the plane appears to be paralyzed. Shortly after Derek returns to the site of the crash, they discover that Mark suffered internal injuries and Cristina must perform a surgical procedure on him with what they have on hand.

In the contrasting storyline, the doctors at Seattle Grace Mercy West have no idea that something has happened to their colleagues and loved ones in the plane crash. The residents who were not on the plane reluctantly prepare to attend a dinner that Dr. Webber is holding for them, a yearly tradition for the exiting resident class. Ben and Miranda fight over the fact that he will be joining a surgical internship in LA. Teddy is offered a job as a chief at MEDCOM, but says she will not take it. When Owen pushes her on the subject, she tells him that she is staying for him, because he needs support. Because of this, Owen fires Teddy, telling her to go be great at MEDCOM.