Modulation of class I and II MHC antigen expression by interferons has been the focus of considerable attention because the regulation of these molecules serves as a useful model system to study factors exerting transcriptional control of gene expression and because of the relevance of these molecules to expression of the neoplastic phenotype. While our knowledge of the molecular mechanisms regulating the ability of interferon to mediate enhancement of MHC genes has increased, this information is primarily based on studies employing established cell lines, and it remains to be determined whether similar controls are also exerted in short term cultured cell lines. In this short review, we have discussed the structural organization of the 5' flanking regions of the MHC genes, with special emphasis on class II genes, and the implications of these data for the transcriptional regulation of these and of other interferon inducible genes. Present evidence indicates the existence of at least four conserved upstream sequences which are shared by interferon responsive genes and which appear to be involved in the transcriptional control of these genes. The pattern of metabolic requirements for IFN-alpha and IFN-beta versus IFN-gamma upregulation of the class I and II MHC genes suggests that the regulation of gene expression by IFN-gamma requires unique regulatory molecules, i.e. newly synthesized proteins, which are not required by IFN-alpha and IFN-beta treated cells. These putative mediators of gene expression are likely to be shared by many of the biochemical induction pathways involved in the regulation of genes which exhibit interferon responsive sequences. However, in addition to common regulatory signals, other specific pathways and possibly additional regulatory sequences, are also required to account for locus--or subunit-specific patterns of antigenic modulation. Future studies are required, including those employing short term tumor cell cultures, to precisely define the molecular details of gene regulation of class I and II MHC genes, as well as other interferon--responsive--genes, by interferons. These investigations will not only prove valuable on a fundamental scientific level, but they will also be crucial for the more effective application of interferons in clinical oncology.