Loss of self tolerance is the key feature of autoimmunity. The p21Ras/MAP kinase pathway plays a major role in the regulation, selection, differentiation and maturation of lymphocytes. Therefore it is conceivable that malfunctioning of this pathway due to permanent or transient signaling defects can lead to an aberrant clonal selection at the thymus or loss of anergy in the periphery. Multiple disease dependent signaling abnormalities along the p21Ras/MAP kinase pathway have been described in different autoimmune diseases including autoimmune diabetes, chronic idiopathic urticaria, inflammatory bowel diseases, celiac disease, multiple sclerosis and systemic lupus erythematosus. This underscores the concept that aberrant function of the p21Ras/MAP kinase pathway may be a common denominator in the pathogenesis of autoimmune diseases. This review focuses solely on evidence derived from animal models and human patients supporting the link between signaling aberrations along the p21Ras/MAP kinase pathway and several representative autoimmune diseases. Significance of these findings and implications regarding the monitoring and treatment of these diseases are discussed.