When Izzie has a mental collapse after Denny's death, Izzie and Cristina turn to Meredith to try and make it better for her. Callie tries to cope with George not returning the three word sentiment she said to him. Meanwhile, back at the hospital, Alex and Addison deal with a baby left in a garbage can at a local high school, Richard receives an ultimatum from his wife, and Derek and George are quarantined in the locker room due to a patient suspected of having the plague.
Patients include a teenage boy with a tree run through him, a man with a tumor on his brain that forces him to be honest, and a patient who goes all out on living before her surgery as the interns begin to go all out on Bailey to ask Izzie to come back to Seattle Grace; Dr. Burke's mother goes all out on breaking Cristina's will; Addison goes all out with the bottle because she found some interesting pocket fanfare in her husband's tuxedo after the prom; and Callie goes all out to make George jealous.
Cristina refuses to quit, like she thinks Preston has. Finn and Derek refuse to quit on Meredith, who insist that they date her. Izzie won't quit standing out front of Seattle Grace, waiting for the time she feels is right to see Dr. Webber. Mark won't quit on giving up on Addison, who now realizes her marriage to Derek is over. And Alex wishes she would quit picking him as her intern in the OB-GYN department.
Denny's father (Fred Ward) visits Izzie and gives her something that will change everything. Meanwhile, Meredith is diagnosed with appendicitis and while waiting for emergency surgery and high on morphine has a talk with Addison for the first time since Addison found the panties. Mark "McSteamy" Sloan starts working at the hospital and Alex wants to work under him instead of Addison because Mark has a patient with severe facial burns. And while Callie and George break up, Meredith finally picks one man.
Derek's sister comes to Seattle for a visit, and seems more into the extended family and gossip surrounding his divorce from Addison than into him. Meanwhile, the interns are not the only ones jealous of Cristina's opportunity to scrub in with Preston on a "Humpty Dumpty" procedure, and Bailey takes it personally when she learns she's been scrubbed, herself. George works with Addison on a very unusual case and Alex envies him.
Derek was looking forward to getting away from it all for a few days until his co-workers all go along on a camping trip. Bailey confronts Cristina and another doctor confronts Izzie about her feelings surrounding Denny. Addison and Callie are confronted by a major problem with a pregnant patient.
A toxic cancer patient immobilizes the hospital, George has an announcement, and Izzie frets that her money wasn't well spent. Meredith, meanwhile, has new issues with her mother and Cristina worries that having a personal life could affect her career.
The interns face a mass-casualty incident while George crosses the professional line with Callie, Cristina asks Preston to let her tell Meredith about their engagement before anyone else finds out, and the Chief dons a new hair style.
Cristina keeps an eye out around the hospital for Meredith to tell her about her impending nuptials. Izzie fights for the life of her patient, still trapped between two vehicles on the ferry and Derek also searches for Meredith, wondering where she's disappeared to. Alex gets the job of notifying friends and family members about the status of loved ones.
A Korean war veteran with an old bullet left in his shoulder is admitted into Seattle Grace. Tensions escalate between Izzie and George, and Callie must reveal a big secret. Alex continues to work with Jane Doe.
Meredith deals with an overbearing step-mother. Christina finds herself caught between Burke and Marlow. Derek fights for the job of Chief. Alex continues the search for Jane Doe's identity. And Izzie's past comes looking for her.
The Chairman of Seattle Grace's board of directors is admitted and all the attendings vie for his favor, Izzy and George keep getting confronted by the results of infidelity, and Preston presses Cristina for a decision.
The interns take the biggest test of their careers, their first-year medical exams, as the residents attend to three injured mountain climbers. Meanwhile Callie's suspicions of George and Izzie grow, and Cristina struggles to write her wedding vows.
The wedding day arrives, and Cristina desperately needs something to take her mind off it, the fourth climber is found and his condition doesn't match the other climbers' stories, and Adele's condition brings a change for Richard.