IFNs are cytokines with important antiproliferative activity and exhibit key roles in immune surveillance against malignancies. Early work initiated over three decades ago led to the discovery of IFN receptor activated Jak-Stat pathways and provided important insights into mechanisms for transcriptional activation of IFN-stimulated genes (ISG) that mediate IFN biologic responses. Since then, additional evidence has established critical roles for other receptor-activated signaling pathways in the induction of IFN activities. These include MAPK pathways, mTOR cascades, and PKC pathways. In addition, specific miRNAs appear to play a significant role in the regulation of IFN signaling responses. This review focuses on the emerging evidence for a model in which IFNs share signaling elements and pathways with growth factors and tumorigenic signals but engage them in a distinctive manner to mediate antiproliferative and antiviral responses.