Primary myelofibrosis (PMF) is a Philadelphia-negative myeloproliferative neoplasm characterized by the presence of increased proliferation of granulocytes and megakaryocytes, osteosclerosis, bone marrow fibrosis and extramedullary hematopoiesis.Patients with PMF may develop debilitating constitutional symptoms, peripheral blood cytopenias and the disease can transform to acute myeloid leukemia.Until recently, there were no approved drugs for the therapy of PMF and the related disorders MF post-polyeythemia vera (MF post-PV) and MF post-essential thrombocythemia (MF post-ET).This scenario started to change in 2005 with the discovery of the JAK2V617F mutation.This mutation leads to constitutive activation of the JAK2 tyrosine kinase, with subsequent activation of intracellular signaling molecules that lead to cellular proliferation and resistance to apoptosis, such as STAT3 and STAT5.The mutation can be found in 90% of patients with PV and 60% of patients with ET and PMF.This was followed by discovery of other mutations in patients with JAK2V617F-negative myeloproliferative neoplasms, such as MPL mutations and JAK2 exonl2 mutation.These mutations were found to have a causal role in the pathogenesis of these disorders, as demonstrated by animal models.More importantly, the discovery of JAK2V617F spurred the development of JAK2 inhibitors for therapy of patients with PMF.These drugs are now currently in clinical trials, and results show that they can reduce splenomegaly, improve constitutional symptom, exercise capacity and the overall quality of life in patients with PMF.JAK2 inhibitors are the first class of drugs approved for therapy of patients with PMF, and show promising results for treating this disorder and other Philadelphia-negative myeloproliferative neoplasms.