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.

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.

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.

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.