Interferons (IFNs) are pleiotropic cytokines with important immunomodulatory, antitumor, antiviral, and growth inhibitory properties. Consistent with the multiplicity of their effects, the IFNs activate several cellular cascades after they bind to their receptors. Although the Jak-Stat pathway is the most studied pathway, it appears that additional signaling cascades play roles in IFN signaling. The phosphatidylinositol 3'-kinase (PI3'K) pathway has emerged as one of the critical players in IFN signal transduction and is the focus of this review. This pathway is activated distinctively from the Stat pathway but plays important roles in the regulation of IFN-dependent gene transcription and initiation of mRNA translation.