Mycobacterial suppression of central nervous system (CNS) autoimmunity has been demonstrated in various experimental models, epidemiological studies, and clinical trials. Recent studies have led to an increased understanding of the cellular and molecular interactions involved in the pathogenesis of autoimmune diseases and of mycobacterial immunity. Here, we review some of the mechanisms by which mycobacterial infection might modulate the clinical course of CNS autoimmunity. A more complete understanding of these mechanisms may lead to the development of novel immunotherapeutic tools for treating autoimmune diseases.