Managing patients with myelofibrosis (MF)-either those with primary MF or those whose MF has evolved from antecedent polycythemia vera or essential thrombocythemia-presents many challenges to the hematologist. Cure is potentially achievable through allogeneic stem cell transplantation, but this therapy is either inappropriate or not feasible for most patients. MF patients suffer from a range of debilitating disease manifestations (eg, massive splenomegaly, cytopenias, constitutional symptoms, and transformation to a treatment-refractory blast phase). Currently available therapies are palliative but can be of significant value to some MF patients for anemia, splenomegaly, or sometimes both manifestations. New medical therapies for MF revolve around three main themes: immunomodulation (to assist anemia), hypomethylation strategies, and (the most robust pipeline) the use of targeted JAK2 inhibitors. These latter agents have shown the ability to improve MF-associated splenomegaly and MF-associated symptoms but do not improve (and may exacerbate) anemia or thrombocytopenia. Future targeted agents, and perhaps combinations of agents that currently show complementary benefits, are anticipated to further enhance the efficacy of medical therapy for MF.