Picks up where the last episode left off. Meredith attempts to work with Addison Shepard. George is pimped out to relay the hospital gossip back to Webber. Meredith and Cristina relate at Emerald City Bar about what dating their respective attendings is like. Cristina ponders her relationship with Burke while trying to make a decision. Meredith is devastated by the latest blow to her love life. Meanwhile, Joe the bartender collapses.

There's tension between Meredith and Addison. We find out why Derek and Addison aren't together. Bailey puts George on an impossible case. The rest of the interns operate on a family that was just in a car accident.

Cristina and Meredith try to figure out if Cristina should tell Burke that she's pregnant right before Cristina faces an emergency. Alex and Izzie get closer while Meredith's mother gets too close.

Train Wreck victims come to Seattle Grace and all staff gets called in. Everyone deals with really weird cases. Except Addison and Izzie. They work with a woman who is pregnant.

Meredith tries to avoid the Shepherds. Cristina and Burke go out on a date and end up getting caught up in their jobs. Derek asks Meredith not to ignore him until Addison comes walking around the corner.

The holiday season has started but not everyone is in a festive mood. This is Alex's last day in the hospital unless he passes his boards practical exam the next day, thus everyone helps him to review so that he succeeds. However, Izzie is not happy about the others helping him and Meredith has to remind her of the true spirit of the Christmas holiday. Justin is in need of a new heart. One is available but he does not want it because he does not believe Santa gave it to him as his mother said. Cristina and Burke, both handling Justin's case, have opposing views on the matter due to their different stances on religion. Despite a reconciliation with his wife, Derek isn't in a festive mood. George has a simple case of a woman who has a bleeding ulcer, he realizes that the ulcer is caused by her entourage but fails to keep them away, with the consequence that it perforates.

Cristina is bothered by a new year's mandatory work limit. Izzie patient, Denny Duquette, wants two things: 1. a heart transplant, 2. Izzie. Addison detests Derek's trailer, Derek visits Meredith's mom, George treats a young teen hermaphrodite frustrated by her pre-pubescence. Other news includes patients doing uncanny things and relationship havoc being wrecked between the doctors, as per usual.

After a series of deaths at the hospital some of the staff become very superstitious. Izzie worries about Denny and gets confronted by Alex. A patient with OCD drives Cristina crazy. Derek and Addison discuss their relationships with Meredith. Richard treats a friend from 17 years ago who reveals a secret about a dark time in his past that involves Ellis. George gets an earful about the women he's not talking to. Burke and Cristina argue about kicking George out.

Denny needs a heart or else. Izzie and George go crazy trying to get him one. Derek has the life of a friend in his hands as he operates on Burke who has been shot. Burke cannot operate on Denny after Denny's heart stopped and now Denny is in a dire condition. Cristina gets put in charge of the ER and she is worried about Burke.

A traumatic car accident fills the ER. Izzie pushes the boundaries of her probation. Cristina has a crisis of conscience about her deceptive teamwork with Burke.

Recent events strain Burke and Cristina's relationship. Mark and Derek must work together when two close-knit brothers seek medical help. One of Meredith's half sisters is admitted to the hospital.

An ambulance crash endangers the lives of the paramedics involved, as Meredith and the Chief work on-site to save them, Bailey treats a patient who refuses her help, and Ava returns for Alex and meets his other girlfriend in the process.

After a roller coaster car falls off the track at the county fair, the doctors at Grey Sloan tend to patients who spark memories about ghosts from their past. The series 300th episode!

Seattle firefighters Ben Warren and Andy Herrera head to Grey Sloan after rescuing two boys who were injured in a house fire; the doctors work on their projects for the surgical innovation contest; Amelia brings Tom Koracick in to consult.

During presentations on Grey Sloan Surgical Innovation Prototypes Day, Arizona shares cookies from an appreciative patient that, unbeknownst to her, contain a special ingredient. Meanwhile, Catherine reveals shocking details to Jackson about his grandfather's past; and Jo steps in mid-operation on a major surgery.