Our knowledge of the substantial complexities of the immune system and understanding of the immunopathogenesis of autoimmune diseases are increasing at such a rapid pace that it is impossible for the non-immunologist to stay abreast of the field. However, there are 2 general principles that are important for clinicians to keep in mind. One is that the immune system regulates itself. The effector arm of the adaptive immune system consists of subsets of lymphocytes that recognize and respond to non-self antigens expressed by infectious agents and malignant cells. Other subsets of lymphocytes regulate the effector arm of the immune system, thereby fine-tuning and limiting responses. A second principle is that autoimmune diseases, such as multiple sclerosis (MS), result from a failure of regulation of lymphocytes capable of reacting to self-antigens. Thus autoimmunity is conceived of as a loss of active tolerance to self-antigens related to activation of effector autoreactive lymphocytes and reduction in activity of regulatory lymphocytes. Much is known about the cellular subsets and molecules involved in autoimmune diseases, allowing rational development of immunotherapies. No better example of this exists than in the expanding armamentarium of immunotherapies for the treatment of MS.