Managing patients with myelofibrosis (MF) (both those with primary myelofibrosis or having evolved from an antecedent polycythemia vera or essential thrombocythemia) present many challenges to the hematologist. MF patients suffer from a variable, but severe range of disease manifestations including massive splenomegaly, cytopenias, significant constitutional symptoms, possible transformation to blast phase and premature death. Cure is achievable through allogeneic stem cell transplantation; yet, this therapy is either inappropriate or not an option for most patients. Current available therapies are palliative, but can sometimes be of significant value to MF patients. The discovery of the JAK2-V617F mutation, and other pathogenetic insights into the pathophysiology of myeloproliferative neoplasms, has ushered in an era of potential new therapies for MF. Over a dozen JAK2 inhibitors are in development, with the leading compounds such as INCB018424, TG101348 and others showing promising early results particularly for control of disease associated splenomegaly and symptoms. Parallel trials with immunomodulatory therapy for MF associated anemia and stromal manifestations of the disease are continuing. The future may well see the approval of a range of agents for MF patients, with differing mechanisms of action, efficacy and toxicity profiles.