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The season follows the story of surgical interns, residents and their competent mentors, as they experience the difficulties of the competitive careers they have chosen. It is set in the surgical wing of the fictional Seattle Grace Hospital, located in Seattle, Washington. A major storyline of the season is the characters adapting to change, as their beloved co-worker Stevens departed following the breakdown of her marriage, O'Malley died in the season premiere—following his being dragged by a bus, and new cardiothoracic surgeon Teddy Altman is given employment at the hospital. Further storylines include Shepherd being promoted to chief of surgery, Seattle Grace Hospital merging with the neighboring Mercy West —introducing several new doctors, and several physicians lives being placed into danger—when a grieving deceased patient's husband embarks on a shooting spree at the hospital, seeking revenge for his wife's death.
The hospital staff is left to deal with the aftermath of George's passing. Hitting the staff hard, they all find unique ways to get through the various stages of grief. George's mom returns, faced with the difficult task of deciding what to do with his organs.
Everyone is struggling after losing one of their own and are turning to any distraction they can find. Meredith and Derek seem to be consummating their marriage anywhere and everywhere, while Cristina and Owen have been instructed to abstain from sex by Dr. Wyatt.
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 Arizonas 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 Izzies 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 Thanksgiving, Christmas and New Year's pass, Miranda gets a visit from her father, William who disapproves of her choices in life. Mark and Lexie cope with an arrival of a woman from his past. Thatcher questions the Chief's recent behavior as Meredith comes to his defense.
Mark flies Addison to Seattle to help with a difficult procedure on his pregnant daughter, Sloan, Owen questions Teddy's motives when she assigns Cristina the lead on a complicated surgery, and Derek's suspicions are raised when the Chief recruits Meredith to assist with a high profile operation on.
After learning of Richard's drinking problem, Derek confronts him for the sake of his friend and the hospital, Izzie returns, hoping to reconcile with Alex, and tensions run high between Teddy, Cristina and Owen in the aftermath of Cristina's startling confession.
As Derek begins his role as interim chief, he faces a potential lawsuit when Bailey and Meredith's patient awakens from anesthesia mid-surgery. Meanwhile, Teddy refuses to place Cristina on her service, as Arizona tests Alex out in Pediatrics, and Mark refuses to speak to a heartbroken Lexie.
It's Valentine's Day, and the doctors must treat dozens of injured people after the roof collapses at a popular romantic restaurant; Derek tries to manage his busy schedule as Chief of Surgery; Meredith wrestles with her new duties as the Chief's wife; and Mark and Callie team up to convince Sloan to do the right thing for her baby.
In his new role as Chief, Derek restores the hospital lecture series, and Richard, Bailey and Callie present to the group pivotal surgical cases from their pasts Bailey reflects on her first days as a shy resident, Callie looks back on a polio case, and Richard recalls a case in which he and Ellis worked on a patient diagnosed with GRID, a virus later called AIDS.
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 who needs an extremely difficult surgery comes to Seattle Grace, and it's Richard and Owen who vie for the opportunity to tackle it. But the decision lies in the hands of Derek, who deems that Owen should take on the surgery, leaving Richard bitter. Meanwhile, Bailey deals with her own personal struggles when she 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 younger brother, Aaron, shows up at Seattle Grace-Mercy West with a hernia, it's up to Alex to get Bailey's approval for his pro bono surgery. Matters are further complicated when Aaron discloses that his family has not heard from Alex since he arrived in Seattle, and parts of Alex's past long kept secret are revealed to his friends and fellow doctors.
Sloan returns to Mark's apartment, just as she's going into labor, and Teddy, Mark and the still-fighting Callie and Arizona are there to help with the birth and to get Mark through his grandson's pending adoption. Meanwhile Teddy sees Derek's invitation to illustrious cardiothoracic surgeon Tom Evans' as a threat to her future employment at the hospital, and the team work on 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 (guest star Demi Lovato) 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.
Seattle Grace Hospital is hit with a crisis like no other in its' history.
Cristina and Meredith's surgical skills are put to the ultimate test.