The development and function of hematopoietic cells depends on complex signaling pathways that are mediated by numerous cytokines and their receptors. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is prominent both in normal hematopoiesis and in hematological malignancies. STATs are phosphorylated on tyrosine residues via JAK kinases and on serine residues by a variety of serine/threonine kinases. STATs then dimerize, translocate to the nucleus and bind DNA, initiating the transcription of target genes. STAT proteins mediate cell growth, differentiation, apoptosis, transformation, and other fundamental cell functions. Recently, mutations in the JAK2 gene driving the proliferation of the neoplastic clone have been identified in myeloproliferative disorders. In addition constitutive activation of the JAK-STAT pathway has been reported in various types of leukemias such as acute myelogenous leukemia, T-LGL leukemia, and multiple myeloma. This review describes the pathophysiological role of this pathway in hematological malignancies and the potential benefits of JAK-STAT inhibition.