The pathogenesis of autoimmunity remains an enigma; however, growing evidence points to a possible involvement of lymphokines both in the initiation phase and especially in the effector stage of many autoimmune diseases. Although no single experimental approach can accurately mimic the highly complex interplay of genetic, hormonal, and immune factors inherent in the development of autoimmunity, several lines of evidence strongly suggest a major role for lymphokines, in particular interferons (IFN), tumor necrosis factor (TNF), and interleukins 1 and 2 (IL-1, IL-2). These include the pleiotropic biologic activities of lymphokines which often synergize and interact, and can mediate several prominent clinical and laboratory manifestations of autoimmunity. Patients undergoing therapy with IFN or IL-2 may develop varied autoimmune syndromes, often an exacerbation of previously latent autoimmunity. Likewise, the administration of IFN to experimental animals can cause or accelerate autoimmune disease and, more importantly, specific lymphokine blockade was shown to be protective. Moreover, in the animal models of autoimmunity and in many patients with autoimmune diseases, increased lymphokine levels can be demonstrated either in the circulation or locally, often correlating with disease activity. Finally, aberrant MHC class II expression on nonlymphoid cells can be identified in the target organs of most autoimmune diseases and extensive data suggest that it can present autoantigen, activate autoreactive T cells, and initiate a cascade of self-propagating autoimmunity. Thus, a local release of IFN-gamma, the major inducer of MHC class II, may be pivotal to the development of organ-specific autoimmunity. The central role of cytokines in lymphocyte traffic into inflammatory sites as well as a growing understanding of lymphokine production patterns by different T cell subsets important in autoimmunity lends further support for this hypothesis, at the same time revealing that certain lymphokines may have a protective inhibitory effect on autoimmunity (e.g., IL-4, TGF-beta). In conclusion, varied data strongly suggest that several lymphokines, produced mainly locally and interacting with each other, have an important role in the pathogenesis of autoimmunity. Although the initiating events and complex interactions remain largely unclear, recent advances are encouraging, and may lead to specific manipulations of lymphokines in the future treatment of autoimmune diseases.