Myeloproliferative neoplasms (MPN) in chronic phase that evolve into blast phase (BP) hold a dismal prognosis and represent an urgent unmet clinical need. The mutational landscape of MPN-BP is distinct from de novo acute myeloid leukemia and offers insight into molecular mechanisms contributing to clonal evolution providing potential novel drug targets. A number of retrospective studies have identified patient- and disease-specific variables associated with increased risk of leukemic transformation (LT) of an underlying MPN. Several prognostic models have been developed to identify those MPN patients at highest risk for LT that may warrant early aggressive therapeutic intervention. Acute myeloid leukemia type induction chemotherapy does not offer a significant survival benefit for MPN-BP unless followed by hematopoietic stem-cell transplantation. Unfortunately, most patients with MPN-BP are not candidates for hematopoietic stem-cell transplantation as a result of advanced age, competing comorbid conditions, or lack of an acceptable donor graft option. JAK2 inhibitor monotherapy is effective in reducing splenomegaly and symptom burden in the majority of treated patients with myelofibrosis, but LT can still occur. High-dose JAK2 inhibitor monotherapy appears tolerable but only modestly active in the treatment of MPN-BP. Current JAK2 inhibitor-based combination therapy approaches are supported by preclinical investigation and are currently being tested in multi-center clinical trials. (C) 2016 Elsevier Inc. All rights reserved.