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There is recent evidence that in addition to the classic JAK/STAT pathways, mitogen-activated proteins (MAP) kinase pathways play important roles in Type I interferon signaling and the generation of interferon responses. In particular, the p38 MAP kinase cascade exerts positive regulatory roles on transciptional activation of interferon-sensitive genes (ISGs) and the induction of the antiproliferative and antiviral properties of interferons. In this chapter, methodologies to detect activation of p38 and various upstream and downstream effectors are provided. Also, the methodological approaches used to examine the role of this pathway on the regulation of hematopoiesis are discussed.