Primary myelofibrosis is a clonal hematopoietic disorder characterized by ineffective hematopoiesis and progressive bone marrow fibrosis. Patients with high risk myelofibrosis as determined by their advanced age, degree of anemia, leukocytosis, constitutional symptoms and high percentage of circulating blasts have a very short median survival of 2 years. In addition quality of life is significantly compromised due to cytokine induced constitutional symptoms, frequent transfusion for cytopenias and bulky splenomegaly. Progression to myelogenous leukemia occurs in about 20% of patients within 10 years of diagnosis and is often fatal. Allogeneic hematopoietic transplantation is the only curative therapy but is limited by patient eligibility, transplant related mortality and graft versus host disease. Androgens, erythropoietin analogues, hydroxyurea, alkylators and spleen directed therapies have all been used with limited efficacy and no curative potential. The discovery of mutations in the hematopoietic progenitors of patients with myelofibrosis, including the JAK2 V617F mutation and others has greatly improved our understanding of the disease and facilitated development of newer targeted therapies. Our article will review new discoveries in the pathogenesis of myelofibrosis and focus on emerging targeted treatments. These novel therapies including oral JAK2 inhibitors, immunomodulators, as well as inhibitors of HDAC and mTOR, in isolation and in combination are likely to improve outcomes in management of this disease.