Recent advances in immunology and molecular biology have contributed to a much greater understanding of the pathogenetic mechanisms of the autoimmune diseases and thus to the development of new rationally-based therapies. Most of the immunosuppressive agents that have been tried in autoimmune disease patients nonspecifically suppress the immune response, often causing various side effects. Autoimmune diseases result from the activation of self-reactive T cells that recognize autoantigens or foreign antigens cross-reactive with an autoantigen coupled with major histocompatibility complex (MHC) products on an antigen presenting cell. It appears possible to modulate T cell activation by interfering with the interaction between T cell receptor and the peptide-MHC molecule complex. A number of sites are potential targets for immunologic intervention, such as MHC molecules, T cell receptor, CD4 and CD3 molecules, adhesion molecules, cytokines and cytokine receptors. In the present review the most important new therapeutic approaches to autoimmune conditions, which appear to be more selective in overcoming the limitations of non-specific treatments, are summarized. They include monoclonal antibodies, cytokines and cytokine-inhibitors, peptides interacting with MHC molecules and T cell vaccination.