Janus kinase 2 (JAK2) is key mediator of signaling through a number of cytokine receptors. Mutations in JAK2 have been found to lead to myeloproliferative neoplasms (MPNs), such as polycythaemia vera and essential thrombocythaemia. These mutations occur predominantly in the pseudokinase domain of JAK2, a domain which negatively regulates the adjacent kinase domain, although the mechanism for this activity is not known. We have used purified recombinant kinase and pseudokinase tandem domains to examine the kinase activity and regulation of JAK2 in haematopoiesis and disease. Further, we have utilized mouse models and in vitro overexpression systems to dissect the interplay between the thrombopoietin receptor, Mpl, and mutated JAK2 in the pathogenesis of MPNs.