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.

Meredith and George are experiencing morning-after tension at home and at work and it has the rest of the doctors wondering what's up. Derek and Addison are experiencing their own version of morning-after tension as a result of Mark's visit to Seattle. Bailey, returning the favor that was done for her during the Code Black situation, must treat Addison for a specific feminine problem. Izzie and Alex are making headway in their relationship until Denny Duquette comes back. Soon Alex is not-so-oddly jealous of the attention Izzie is showing to Denny. Someone finds comfort in confiding in a patient who is going through an ordeal of his own. Burke deals with a patient and gets to observe the patient's unstable relationship with his fiancée.

The doctors are up to their necks in their usual levels of drama. Meredith is dealing with the backlash of sleeping with George, George and Burke are bonding in ways that bother and creep out Cristina, Cristina gets stuck on diaper duty, Bailey gets involved in a case even though she's still supposed to be on maternity leave, Addison and Derek have a talk, and Izzie is still flaking on Alex for Denny Duquette, the heart patient who didn't get a heart. In the patients-of-the-week department we've got a very pregnant woman, a hockey player who desires medically unnessasary amputation, and a woman with a fork in her neck who happens to be dying and has a struggling marriage.

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.

Meredith and Izzie take up knitting. Derek operates on Andrew, a spelling bee champ with a serious head injury. Bailey gets in on Andrew's surgery because she's worried that her coworkers won't recognize her Nazi-status now that she's a mother. Addison's patient has an unborn baby with medical issues. After Alex fails to bite his tongue when a terminal patient routinely lies to her daughter about her health he gets a lesson in bedside manners from Burke. George also begins to overstay his welcome at Burke's apartment after Callie visits him. Meredith has more confusing and uncomfortable encounters with members of her family. One of the female doctors meets a veterinarian named Finn. Izzie flirts with Denny and they play more naughty-Scrabble. Meredith, Derek, and Addison sarcastically take another small stab at their friendships.

Addison's patient is a Catholic mother of seven. Addison gets in trouble after learning that the patient's husband won't use contraceptives. Derek treats a divorce attorney who asks if Derek is in need of her services. While Izzie and George are talking about their personal lives they "overhear" part of Derek's conversation with the divorce attorney who calls herself one of Seattle's best. Alex gets in trouble with Addison yet again for not being able to keep his mouth shut when other people think he should. A legendary jazz musician refuses to see medical reason. The musician is Burke's musical hero. Finn makes Meredith breakfast.

The staff attends to an intern from another hospital who has short-term memory loss. This intern, named Marshall, also has caused a car accident that involved a married couple, their unborn baby and the woman's parents who the staff are also treating. The pregnant woman is named Melanie and she will die but her baby may survive. One of the female interns meets up with a woman from her past who is planning on having a family of her own. Cristina is in a good mood although Alex, Izzie, George, and Meredith are having problems but in the meantime Burke hasn't forgiven Cristina for her late night faux pas. Meredith and Izzie are making fun of Callie's household habits and George and Callie are having a fight because of George's roommates. Addison is continuing to own Alex and he's upset about it. Denny has an outburst at Izzie and Derek has an outburst at Meredith.

George and Derek work together, Denny still doesn't have a heart, and Meredith gets paired with Callie. A 12-week pregnant girl dies in the O.R. and her parents try to keep the baby alive. This causes tension between Derek and Addison. One doctor's overreaction unites two bickering patients. Finn is still treating Doc for medical problems.

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.

This episode is the second part of a two-hour season finale. Richard tries to get information from Addison about a family member's condition. Callie and George have a talk about his feelings. Meredith and Derek have a talk about Doc.

Meredith is still underwater, but nobody seems to notice. Her worsening condition makes her rescuing an urgent matter. Derek finds her coat on a man she had helped, and starts looking for her and, much to his shock, the little girl Meredith took care of suggests that she is in the water. Derek saves her, but she is almost dead, due to hypothermia. Izzie has to perform brain surgery on a man stuck between cars, as he begins to experience seizures. She drills holes into his head, perforates his skull and ultimately saves his life before he is rescued and transferred to Seattle Grace Hospital. George lies to the woman whose son he had been looking for, in order to get to surgery, but still doesn't have any luck in locating him. Alex finds no hope in searching for the pregnant Jane Doe's family as she undergoes surgery. The interns find out about Meredith's situation and express their hopelessness. She wakes up in what appears to be limbo and meets her deceased acquaintances.

Everyone is pushing for Meredith to survive, or in this case to be revived. People are still dealing with the fallout from the ferry disaster. A young man named Lucas is having problems with brain-mouth coordination. Someone else dies.

When the Chief makes an announcement that a solo surgery is up as an award, the residents are sent into a frenzy all trying to get an edge over one another. Meanwhile, Derek asks Bailey for advice after Cristina continues to interfere in his relationship with Meredith. Elsewhere, Erica uncovers a shocking connection between a resident and a patient.

One of Meredith's oldest friends, Sadie, becomes an intern at Seattle Grace, but Mer's friends are less-than-welcoming to her.

Meredith, Cristina and Bailey come to Lexie and Sadie's rescue when a routine surgery goes horribly wrong, as Owen and Derek treat a man seriously injured while sleepwalking and Mark comforts the sleepwalker's distraught daughter.

Cristina is awarded the first solo surgery among the residents, but she is forced to give it up and choose her replacement; Lexie is impressed when Mark performs a cutting-edge procedure; Callie doesn't know if Sadie is friendly or flirtatious.

Bailey teams with Seattle Grace's new pediatric surgeon, Dr. Arizona Robbins, to save the life of a young patient near and dear to her heart, as the admittance of a death row inmate at the hospital stirs anger in Derek and further erodes Meredith and Cristina's friendship; meanwhile, Callie and Sloan work as a team to fight their respective attractions to Sadie and Lexie, and Izzie tells Alex that she's seeing Denny.

Derek's mother, Carolyn, makes a surprise visit to Seattle and meets Meredith for the first time, as Mark tries to conceal his relationship with Lexie from her as well; meanwhile, death row inmate William wishes to donate his organs to Bailey and Arizona's patient, as Owen and Cristina try to go on their first date.

Bailey grows desperate as a patient's condition becomes more and more dire. Everyone in the hospital is stepping up to try to find the boy a new organ donor, including Meredith, who considers a death row patient's wish to die before execution. Meanwhile, an injury leaves Mark in a compromising position in the OR and Cristina awkwardly avoids Owen.

As Meredith, Derek and all of their friends prepare for the big wedding, a group of college students, injured in a car crash as they were heading to their graduation ceremony, is admitted to the ER. Meanwhile, Izzie fears the worst when she begins experiencing familiar symptoms.

In the first part of the two hour season finale, Izzie spends time with a fellow cancer patient and contemplates whether or not to undergo a risky surgery, as Mark is ready to take his relationship with Lexie to the next level and a patient makes Owen reassess his place at Seattle Grace.