Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm diagnosed de novo or developed from essential thrombocythemia (ET) or polycythemia vera (PV). Average survival of a patient with MF is 5-7 years. Disease complications include fatigue, early satiety, pruritus, painful splenic infarcts, infections and leukemic transformation. Allogeneic hematopoietic stem cell transplant (HSCT) is the only potentially curative option for MF, but carries a risk of treatment-related mortality and is reserved for the few high-risk patients fit enough to endure the procedure. Other traditional therapies are palliative and supported by few randomized, controlled trials; thus, novel treatment strategies are needed. Discovery of the Janus kinase 2 (JAK2) gain-of-function mutation, JAK2V617F, in the majority (50-60%) of patients with MF led to increased understanding of the biology underlying MF and the development of JAK2 inhibitors to treat MF. Recent Food and Drug Administration (FDA) approval of the first JAK2 inhibitor, ruxolitinib, signaled a new era for treatment of MF. Additional JAK2 inhibitors, such as SAR302503, may become commercially available in the near future, and their distinct pharmacologic and efficacy profiles will help determine their use across the patient population. Data on JAK2 inhibitors, their role in an evolving treatment paradigm, and future directions for treatment of MF are discussed.