The immune system may act as friend or foe. Fortunately, it serves to protect the individual from foreign pathogens. During development, the immune system is programmed and learns to distinguish self from non-self. Thus, tolerance of self can be denned as a state of antigen-induced unresponsiveness. This process is dependent on an interaction of the major histocompatibility complex plus antigen plus T cell receptor. Under certain conditions, tolerance fails (or breaks down), resulting in a state of autoimmunity. In simple terms, autoimmunity is an immune reaction to self. This article reviews the pathophysiology of autoimmune disease, the major autoimmune polyglandular syndromes that include the ovary, and the autoimmune etiology of ovarian failure.