The human Major Histocompatibility Complex (MHC) region comprises several clusters of genes that play a critical role in the host immune defense. As antigen presenting molecules, the products of the MHC class I genes are essential for the cellular immunity against  viral-,  tumor-  and  allo-antigens,  and  for development of the CD8⁺ T cell compartment. The MHC class I region represents one of the best-studied polymorphic genetic systems because of this key role in adaptive immunity. The genes encoding MHC class I molecules are tightly regulated during development and in fully differentiated cells. Transcription of MHC class I and β₂m genes is controlled by a number of cis-acting regulatory promoter elements that include binding sites for NF-ĸB, such as found in the enhancer A, and an interferon stimulated response element (ISRE). Notably, recent studies on the transcriptional control of MHC class I and β₂m genes have shown that MHC class I and β₂m promoters also contain an SXY regulatory module that is shared with the promoters of MHC class II and its accessory genes. These studies have provided novel insights into the mechanism of transactivation of MHC class I and β₂m promoters. In this review, the authors discuss the proteins that interact with the two clusters of conserved regulatory elements in the proximal promoter region in relation to transactivation of the various MHC class I loci and their cooperation in promoter assembly of general and gene-specific transcription factors.