Studies on the mechanisms by which IFNs exert their antitumor activity have helped to understand host resistance to tumor emergence and also define cellular actions of interferon-stimulated gene (ISG) products (see Table 53-1). These latter proteins underlie not only the antitumor and immunoregulatory actions but also the antiviral effects of IFNs. More than a thousand genes regulated through IFN signaling pathways now have been identified. ^1,2 Suppression of IFNs and influences on their regulated gene products in and by malignant cells is emerging as an important contributor to the development of some human cancers (Table 53-2 ). Germ-cell mutation of an ISG RNASEL increases risk for prostate, breast, head and neck, and pancreatic carcinomas. ^3–6 Gene expression profiling and cytogenetic analyses have identified somatic homozygous deletions in the locus for IFNs at 9p21 and mutations of ISGs in melanoma, colon, lung, and hematologic malignancies. ^7–12 Epigenetic and genetic silencing of IFN signaling also likely influences tumor development. ^11,13–15 Activated natural killer (NK) and T cells have a critical role in the production and action of IFNs for potent immunomodulatory roles in the protection from chemical carcinogenesis and in controlling the growth of syngeneic and transplanted tumors. In addition to being a primary source for the production of IFNs-α and IFN-β, dendritic cell maturation is also influenced by IFNs. ^16–19 These actions of endogenous IFNs-α, IFN-β, and IFN-γ are probably the basis for the effectiveness of IFNs and/or inducers in suppressing tumor emergence and progression. ^20–22 These immunomodulatory actions, however, may or may not be identical to those resulting in clinical tumor regression with IFNs administered as single agents or in conjunction with other modalities of therapy.