MHC class I and class II molecules play essential roles in the adaptive immune response by virtue of their ability to present peptides to T lymphocytes. Given their central role in adaptive immunity, the genes encoding these peptide-presenting molecules are regulated in a tight fashion to meet with local requirements for an adequate immune response. In contrast to MHC class I gene products, which are expressed on almost all nucleated cells, constitutive expression of MHC class II molecules is found only in specialized antigen-presenting cells of the immune system. Expression of both classes of MHC molecules can be induced by immune regulators and upon cell activation. A set of conserved cis-acting regulatory promoter elements mediate the transcription of MHC class I and beta2-microglobulin genes. Of these regulatory elements, the promoters of MHC class II and accessory genes also have the SXY module. The MHC class II transactivator (CIITA) is essential for the activation of MHC class II promoters, and it functions through protein-protein interactions with regulatory factors bound to the SXY module. Given the central role of CIITA in these regulatory processes, it is of interest to identify the DNA-binding factors and co-activators that assemble on CIITA promoters in a cell-type-specific fashion. Accordingly, recent studies include investigations into chromatin remodeling and epigenetic control mechanisms that modulate cell-type-specific transcriptional regulation of genes involved in antigen presentation.