The BCR-ABL-negative myeloproliferative neoplasms (MPNs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis have an increasing predisposition over the course of a patient’s illness to transform to overt acute leukemia what is referred to as MPN-Blast Phase (MPN-BP). Although the transformation of MPNs into acute leukemia is by itself a very rare phenomenon, once this has occurred, it is associated with poor response to chemotherapy and a high risk of relapse after allogeneic stem cell transplant (ASCT) and hence resulting in very poor survival in most cases. Pathogenetic mechanisms which lead to an MPN progressing to MPN-BP are incompletely understood but seem to correlate with accumulation of additional karyotypic abnormalities as opposed to increases in MPN-associated molecular lesion burden (such as JAK2 V617F). The development of MPN-BP is heralded by worsening cytopenias, constitutional symptoms, and a very poor survival despite therapeutic intervention. Risk factors for developing MPN-BP include both features at diagnosis (such as increased peripheral blood blasts, karyotypic abnormalities, and thrombocytopenia), as well as exposure to established agents which enhance leukemogenesis (i.e., P-32 and alkylators). Current therapies for the MPNs are limited, and no therapy other than an ASCT has clearly altered the natural history of these neoplasms. Therefore, an overall management plan that incorporates the possibility of ASCT should be developed for patients with MPN-BP at the time of diagnosis. However, it is not all dark and gray in the MPN-BP world; in last 6 years, we have made more advances in the treatment of MPNs than in the last 60 years. Multiple avenues of therapeutic investigation are ongoing to treat, or prevent, MPN-BP including early allogeneic stem cell transplantation, hypomethylating agents, and JAK2 inhibition.