Fragments of foreign antigen are detected by CD4+ helper T cells via the T cell receptor for antigen in the context of major histocompatibility complex (MHC) class II molecules. Very few cells normally express class II MHC molecules, and these cells play critical roles in antigen presentation and in the thymic selection of T lymphocytes before their exit into the periphery. Because of the central role the class II MHC molecules play in immune system function, it is not surprising that the lack of expression of these molecules results in a severe combined immunodeficiency disorder (called bare lymphocyte syndrome) and that the aberrant expression of the molecules is frequently observed in the target organs of various autoimmune disorders (e.g., multiple sclerosis and rheumatoid arthritis). Because both classes of disease could conceivably be treated by molecular approaches targeted at either restoring or inhibiting expression of class II MHC genes, there has been an intense effort during the past decade to elucidate the regulatory mechanisms of class II MHC genes. An analysis of recent advances in this effort is provided in this review article.