The Seattle Grace staff has to deal with the aftermath of George's tragic death. As the news hits the staff hard, they all must find a way to get through the stages of grief. Later, George's mother arrives at the hospital to decide what to do with his organs.
Though time has passed since George's death, everyone continues to struggle with his passing by finding distractions to keep themselves occupied. Meredith and Derek cope by consummating their marriage anywhere and everywhere, while Dr. Wyatt suggests that Cristina and Owen abstain from sex.
Several weeks after her near-death experience, a recovering Izzie returns to work. Meanwhile, nervous that there will be layoffs in the hospital in the wake of an announcement from the Chief, the Seattle Grace residents compete to survive the cuts, including Cristina, who attempts to work alongside Arizona in pediatrics. And Bailey and Alex's patient's already complex case is further complicated by her schizophrenic son.
When Meredith and Lexie's father, Thatcher, returns to the hospital with a failed liver, it's up to Meredith to save his life. Meanwhile, Izzie empathizes with a patient riddled with tumors, as Mark, annoyed with Cristina's competitive zeal, tricks her into assisting on an unusual surgery.
The residents of Seattle Grace and Mercy West vie for surgeries and their careers as day one of the hospital merger begins. Meanwhile, Arizona stands by an enraged Callie when her father, Mr. Torres, employs a priest to help convince her to date men, and Izzie experiences the brunt of her new surgical competition.
After a burn victim unexpectedly dies in the midst of a chaotic ER, the Chief and board member Jennings interrogate the residents to find the culprit, as all the Mercy West and Seattle Grace resident defends their actions in an effort to save their jobs.
When Isaac has an inoperable tumor wrapped around his spine, he wants Derek to do the impossible. Derek tests the Chief's authority when Richard objects to moving forward with the risky surgery.
A generous 25 million donation is offered to Seattle Grace by the parents of Arizona's 10-year-old patient, she finds herself in a conflict of interest when his condition worsens. Cristina tests her boundaries with Owen at the hospital. Alex is left with all of Izzie's hospital bills to contend with.
Owen recruits Dr. Teddy Altman a former Iraqi veteran, as the new cardiothoracic surgeon, Cristina questions her abilities in the E.R. and relationship with Owen. Izzie returns to Seattle Grace with her high school mentor seeking treatment for his dementia. Richard's responsibilities, post-merger, are taking a toll on him.
As the holidays come and go, Miranda has a surprise visit from her father, William, who has a strong disapproval of her choices in life. Mark and Lexie must cope with a person who re-enters Mark's life, and Thatcher Grey questions the Chief's behavior, but Meredith is quick to come to the Chief's defense.
In order to get help with a difficult procedure on his pregnant daughter, Mark flies Addison to Seattle, while Owen questions Teddy's motives after she assigns Cristina the lead on a complicated surgery. Meanwhile, Derek's suspicions are raised when Meredith is recruited by the Chief to assist with a high-profile operation.
Derek confronts Richard over his alcoholism in an attempt to help his friend and the hospital. Izzie returns to reconcile with Alex, and tensions between Teddy, Cristina and Owen escalate.
Derek steps in as interim chief as he faces a huge law suit when a Bailey and Meredeth's patient wakes up on the table.
Valentine's Day hits Seattle Grace with a bang when the roof of a popular romantic restaurant collapses and the doctors have to deal with the fallout. Derek continues to struggle in his new position as his busy schedule takes its toll, while Meredith faces the pressure of being the chief's wife. Meanwhile, Mark and Callie try to convince Sloan to do the right thing for her baby.
Derek reinstates hospital lectures, leading the doctors to recount stories of their past - Bailey tells of her days as a timid young resident, Callie reflects on a polio case, and Richard recalls an AIDS patient he treated with Ellis.
When famous surgeon Dr. Harper Avery is rushed to Seattle Grace-Mercy West, the staff is surprised to discover that one of their own is related to this legend, and his unorthodox request for his surgery causes tensions t between Derek and Richard. Meanwhile Callie and Arizona try to help Teddy and Sloan move on from their pasts and find greener pastures.
A patient arrives at the hospital in need of a complex surgical procedure, and Richard is furious when Derek chooses Owen to do it over him. Meanwhile, Bailey nervously prepares for another date with Ben.
When Teddy's patient seeks to end treatment and her life, she turns to Hunt for help. The situation triggers Hunt's memories of his life at war and his past relationship with Teddy. Meanwhile, Callie and Arizona have a difference in opinion on what their future holds, and Richard tries to adjust to his role as a surgeon.
When Alex's brother shows up at the hospital with a hernia, Alex must get Bailey's approval for pro-bono surgery; parts of Alex's past are revealed to his friends and colleagues.
Sloan is in labor and Mark, Teddy, Callie and Arizona come to help. The doctors are faced with a the case of a crab boat captain who has been stabbed with a giant shark hook.
Bailey preps the team with mandatory sensitivity training prior to admitting a 700-pound patient with compounded medical issues, and the case proves to be challenging in every sense of the word. Meanwhile Derek has to come face to face with a former patient's husband in a wrongful death deposition, and spending time with a heart patient's daughter opens up some old wounds for Cristina.
An elderly patient admitted into the E.R. for a heart condition sees a familiar face, a long lost love who happens to be in the E.R. as well for a fractured arm, and the staff find themselves caught up in their love story. Meanwhile, Karev treats a troubled teenage patient Hayley, whose parents brought her in for schizophrenia, and Meredith can't help but tell Cristina about her suspicions of Owen - which inevitably messes with Cristina's head.
In the first hour of the two-hour season six finale, Seattle Grace Hospital is hit with a crisis like no other in its' history. The season finale will see Seattle Grace inundated with victims of a multi-car pile-up. One of the doctors will also be devastated by a fire in her house.
In the second hour of the season finale, Cristina and Meredith's surgical skills are put to the ultimate test.