The Janus kinases (JAKs) enzymes are a family of cytosolic tyrosine kinases that are associated with membrane receptors and play a critical role in the rapid transduction of signals from cell surface to the nucleus. There are four different tyrosine kinases (Tyk2, Jak1, Jak2, Jak3) that share significant structural homology with each other. Binding of cytokines or growth factors to their cognate receptor activate JAK kinases, which in turn mediate the subsequent tyrosine phosphorylation of STAT proteins. Phosphorylated STAT proteins form dimers, translocate to the nucleus, and bind to specific DNA elements to induce or modulate expression of target genes. Aberrant activation of JAK kinases has been implicated in many hematological malignancies and carcinomas. There is also accumulating evidence that constitutive activation of different Jaks and Stats mediate neoplastic transformation and promote abnormal cell proliferation in various malignancies. This review will discuss the role of various Jak-kinase dependent signal transduction pathways in malignancies as well as therapeutic implications of the recent advances in the field.