Derek Christopher Shepherd is the Head of Neurosurgery and board director at Grey Sloan Memorial Hospital. He is married to Meredith Grey and they have a little girl named Zola Grey Shepherd and a newborn son named Derek Bailey Shepherd.

Although he is sometimes annoyed by his overbearing mother and sisters, he is nonetheless aware of their closeness and has no doubt that all four of his "very girly" sisters would be at his bedside if he were ever hurt or sick. His profound hurt over Mark's affair with Addison back in New York is compounded by his view of Mark as his brother, the one constant male influence in his life since the death of his father as a child.

At Seattle Grace, he managed to stay friends with Addison, even after their divorce, and was best friends with Preston Burke, but was left without friends when they both left Seattle Grace Hospital. He was broken up with Meredith, Bailey didn't want to have a drink with him, and the Chief said he didn't drink. With nobody to talk to, Derek started to talk to Mark again, and they slowly began to rebuild their friendship and soon enough became best friends again. After getting back together with Meredith, he became friends with her friends, primarily Cristina, Alex, Izzie and George, and also bonded with Meredith's sister Lexie Grey following her arrival at Seattle Grace and within the wake of her mother's death. After a rough start with Owen Hunt, Both Derek and Mark began forming strong bonds of friendship with him.

When Richard began slipping back into the state of a severe alcoholic, Derek was adamant on Richard seeking treatment for his condition, even if it meant jeopardizing Richard's career in the process. When the hospital board learned that he'd begun drinking again, they presented to him the option of retiring. Derek, on the other hand, stood by the plan that Richard enter a rehab program, sober up, and return to his position as Chief of Surgery. While still in denial of his predicament, Richard accuses Derek of forcing his problems out into the open so he could get his hands on the position as Chief. While Derek admitted that he did want the job, he still stood by the plan of Richard entering rehab so that Richard could eventually return as Chief. In Richard's absence as chief, Derek assumed the role temporarily.

Professionally, Derek is regarded one of the best neurosurgeons in the world. His services result in two million dollars worth of annual revenue for the hospital. Derek has performed numerous complicated, risky procedures, including a stand-still operation, two double-barrel brain bypasses, and separation surgery for adult conjoined twins. His confidence was shaken slightly when his surgery to repair a gunshot injury on a colleague, Preston Burke, resulted in Burke's hand developing a tremor, but Derek remains a competent and skilled surgeon who has not forgotten the importance of compassion and bedside manner when dealing with patients. Derek's professional life hit an obstacle when Richard Webber announced his plans to retire. Derek had originally been promised the chief position when Richard offered him the job in Seattle, but was surprised to find that the position had instead been offered to Preston Burke. When word got out about Richard's retirement, Addison and Mark joined in the race for chief. Eventually, Webber came to a decision. He offered the Chief position to Derek, but Derek declined it and instead encouraged Richard to stay on as Chief.

Derek's confidence took another blow when he accidentally clipped an aneurysm on a pregnant woman during surgery, remarking that it was unlike him. While Addison is in Seattle tending to her brother, she consults, and Derek suggests a risky procedure, despite knowing nothing of the procedure or its risks, feeling immensely guilty over clipping the aneurysm and will do all in his, or Addison's, power to keep her alive. Unfortunately, she dies later in surgery, upsetting her husband, who calls Derek a murderer. This sends Derek into a depression. Later, at a deposition, he learns more of his patients have died than survived and he walks out of Seattle Grace.

While in his depression, pushing Meredith away and being almost constantly drunk, Bailey sends Callie and later Owen to try and bring him back. Derek, however, talks to both of them and makes them feel depressed over those who they have "killed", prompting them to start drinking with him, until Richard comes and shouts at him, telling him he is in a much better position than he was. He is promoted to Acting Chief of Surgery, after the Richard is forced into rehab to keep his job. After Derek orders a patient to be taken off life support against her husband's wishes, the husband returns to the hospital and searches for Derek, shooting several surgeons on his way to him. The shooter eventually finds Derek and shoots him, forcing Richard to take over as interim Chief during Derek's absence from work. Derek returns and immediately quits as Chief, admitting that he hates the job and just wants to go back to being a neurosurgeon.

Over the course of his career, Derek has been the lead surgeon on two clinical trials. The first was initiated by Meredith—publicized as "The Shepherd Method", it is the injection of a live virus into a brain tumor as treatment. The second clinical trial was for the development of a cure for Alzheimer's, which he was able to fund through his earned Phillip's Grant. Derek was then blacklisted by the FDA after it was revealed that the trial was tampered with. He sent it to a Carl Baumann in Phoenix to continue the trial.

After the plane crash, Derek wasn't able to perform surgery for a while. During this time, he was teaching residents and helping Callie Torres with her trial on better prosthetics. The work on this trial led him to the development of brain sensors, which caught the attention of the president of the United States. The president requested him for a brain mapping project and gave him the opportunity to run it.