Several autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), are characterized by B cell hyperactivity, polyclonal activation, and autoantibody synthesis. Overt B cell clonal expansion occurs in a minority of the patients, while at the tissue level clonotypic B cells may be more easily detected in the majority of patients. The data available suggests that antigen-driven B cell expansion, eventually leading to somatic mutation and transformation, is the main event. Immunosuppressive drugs known to increase chromosomal damage and to lead to earlier transformation should therefore be avoided, unless strictly necessary to preserve vital organ functioning. New immunosuppressive drugs such as methotrexate, cyclosporine A, and Rapamycin are promising for they seem to offer effective control of disease-related organ damage with acceptable side effects. The B cell lymphoproliferative diseases occurring under treatment seem to remit spontaneously after prompt drug withdrawal. Close surveillance, employing new techniques capable of detecting early B or T cell clonal expansion, may allow better monitoring of possible complications. Biological agents such as alpha-interferon and monoclonal antibodies (which are directed against specific immunological mediators and thus target-selected steps of the immune-inflammatory process) have opened promising new research topics in all these diseases.