Interferons (IFNs) are cytokines that regulate a variety of biologic effects, including cellular antiviral responses, inhibition of proliferation, induction of differentiation, and immunoregulation, via different mechanisms. In order to mediate such pleiotropic effects, IFNs trigger numerous signaling events. One way for IFNs to regulate cellular functions is through activation of mitogen-activated protein (MAP) kinases. Three major cascades of MAP kinases are known. The c-Jun NH(2)-terminal kinase (JNK) cascade, the extracellular signal-regulated kinase (ERK) cascade, and the p38 MAP kinase cascade. ERK and p38 MAP kinases are activated in response to type I IFNs and participate in the regulation of cellular responses. In this review we discuss recent findings on the role of the p38 MAP kinase pathway and its function in mediating IFN-dependent biologic effects. We further dissect and discuss the roles of upstream and downstream components of the p38 MAP kinase in the control of cellular responses triggered by IFNs.