The clinical course of polycythemia vera (PV) is marked by a high incidence of thrombotic complications; fibrotic and leukemic disease transformations are additional causes of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis; leukocytosis and high JAK2 V617F allele burden are currently being investigated for additional prognostic value in this regard. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use raises the risk of transformation into acute leukemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients should be treated with phlebotomy and low-dose aspirin. Cytotoxic therapy is indicated in high-risk patients, and the drug of choice is hydroxyurea because of its efficacy in preventing thrombosis and low leukemogenicity. Interferon-alpha should be reserved for selected categories of patients due to high cost and toxicity. The demonstration of JAK2 V617F mutation in the vast majority of PV patients opens the avenue for the development of promising new molecularly targeted drugs.