Originally identified as regulators of the type I Interferon system, the nine mammalian members of the Interferon Regulatory Factor (IRF) family are transcriptional regulators with multiple biologic functions, among which the best known are those involved in initiating and regulating many aspect of host immunity, downstream pattern recognition receptors in response to cell injuries. In addition, these versatile proteins also regulate cell differentiation, cell growth and apoptosis in several cell types, and when mutated or disregulated significantly contribute to susceptibility to and progression of several cancers. IRF-1 is the most versatile member of the family, not essential for IFN gene expression and implicated in a variety of cellular functions spanning from the development and function of various immune cells to tumor suppression activity. IRF-3, IRF-7 and IRF-9 are more specifically involved in IFN induction and antiviral responses while IRF-5 is the regulator of inflammatory cytokines expression downstream pattern recognition receptors and IRF-6 is implicated in epithelial differentiation. IRF-8 as IRF-1 is considered a tumor suppressor gene, while IRF-2 and IRF-4 have generally oncogenic activity.The present review focuses principally on the current knowledge on IRF genetic characteristics, including mutations, polymorphisms and epigenetic regulation that are implicated in oncogenesis.