Abstract Transcriptional regulation is a consequence of the combination of both activation and repression for establishing specific patterns of eukaryotic gene expression. The regulation of the expression of type I interferon (IFN-A and IFN-B) multigene family is controlled primarily at the transcriptional level and has been widely studied as a model for understanding the mechanisms of stable repression, transient virus induction and postinduction repression of the genes. The positive and negative regulatory elements required for this on/off switch have been defined within a complex 5′ upstream region of their transcription start site. The differential expression pattern of type I IFN genes is thought to involve both substitutions in the virus responsive element (VRE) and presence or absence of negatively acting sequences surrounding the VRE. In this review we discuss several mechanisms of negative regulation due to the existence of common or specific elements in the IFN-B and IFN-A genes and we summarize recent studies on transcriptional repressors that bind to these promoters.