In recent years, prison officials have increasingly turned to solitary confinement as a way to manage difficult or dangerous prisoners. Many of the prisoners subjected to isolation, which can extend for years, have serious mental illness, and the conditions of solitary confinement can exacerbate their symptoms or provoke recurrence. Prison rules for isolated prisoners, however, greatly restrict the nature and quantity of mental health services that they can receive. In this article, we describe the use of isolation (called segregation by prison officials) to confine prisoners with serious mental illness, the psychological consequences of such confinement, and the response of U.S. courts and human rights experts. We then address the challenges and human rights responsibilities of physicians confronting this prison practice. We conclude by urging professional organizations to adopt formal positions against the prolonged isolation of prisoners with serious mental illness.