The main function of major histocompatibility complex (MHC) class II molecules is to present processed antigens, which are derived primarily from exogenous sources, to CD4(+) T-lymphocytes. MHC class II molecules thereby are critical for the initiation of the antigen-specific immune response. Besides antigen presentation, growing evidence is showing that ligation of MHC class II molecules also activates intracellular signaling pathways, frequently leading to apoptosis. Constitutive expression of MHC class II molecules is confined to professional antigen-presenting cells (APC) of the immune system, and in nonprofessional APCs MHC class II molecules can be induced by a variety of immune regulators. Interestingly, activated T cells from many species, with the exception of mice, synthesize and express MHC class II molecules at their cell surface. In this review, we discuss our current knowledge on the transcriptional regulation of MHC class II expression in activated human and mouse T cells, and the contribution of DNA methylation of the T-cell employed class II transactivator promoter III to the MHC class II deficiency of mouse T cells. We also discuss the proposed functions of the activated T cell synthesized and expressed MHC class II molecules, including antigen presentation, T-T cell interactions, and MHC class II-mediated intracellular signaling.