Major histocompatibility complex (MHC) is a conglomerate of genes that play an important role in recognition of self and nonself. These genes are under tight control. In this review we have discussed the transcription processes regulating MHC gene expression. Various biological or chemical modulators can modulate MHC gene expression. The promoter region of class I genes can be activated through several pathways. Hence, these genes are not typical "domestic" genes. Extensive studies on regulation of MHC class I expression, using transfection techniques and transgenic animal models, have resulted in identification of various cis-acting sequences involved in positive and negative regulation of class I genes. Work is in progress to identify the transacting proteins that bind to these sites and to delineate the mechanisms that regulate constitutive and inducible expression of class I genes in normal and diseased cells. It has been seen that various biological molecules (IFN, GM-CSF, IL-2) and other chemicals up-regulate the MHC expression. If the exact mechanisms are known by which the expression of class I genes is up regulated, the efforts can be made to balance the beneficial and toxic effects of biological molecules with one another, which may facilitate the use of combination of these molecules in subpharmacological doses (to eliminate toxicity) for early and better management of neoplastic diseases, as it is well-known that during malignancy MHC gene expression is down-regulated. In the future, the use of transgenic and knockout mice will be useful in acquiring a better understanding, which may further help in cancer therapy.