Autoimmune diseases are caused by immune cells attacking the host tissues they are supposed to protect. Recent advances suggest that maintaining a balance of effector and regulatory immune function is critical for avoiding autoimmunity. New therapies, including costimulation blockade, regulatory T cell therapy, antigen-specific immunotherapy, and manipulating the interleukin-2 pathway, attempt to restore this balance. This review discusses these advances as well as the challenges that must be overcome to target these therapies to patients suffering from autoimmune disease while avoiding the pitfalls of general immunosuppression.