The diagnostic approach to a patient with polycythemia has been greatly simplified by the introduction of new genetic testing in addition to traditional tests, such as measurement of red cell mass and serum erythropoietin (Epo) level. Clonal erythrocytosis, which is the diagnostic feature of polycythemia vera (PV), is almost always associated with a JAK2 mutation (JAK2V617F or exon 12). Therefore, in a patient with acquired erythrocytosis, it is reasonable to begin the diagnostic work-up with JAK2 mutation analysis to distinguish PV from secondary erythrocytosis. The clinical course of PV is marked by a high incidence of thrombotic complications that represent the main cause of morbidity and mortality in these patients. Blood hyperviscosity as well as platelet and leukocyte quantitative, and qualitative abnormalities play a major role in the pathogenesis of thrombophilia. Prevention of vascular events and minimizing the risk of disease transition into acute leukaemia are the main targets of the whole PV treatment strategy. This can rely on the use of low-dose aspirin in most patients, while the choice of the optimal cytoreductive strategy is based on the individual vascular risk. Phlebotomy is still the preferred treatment in subjects at low risk, while hydroxyurea or pipobroman is usually administered to most elderly subjects or subjects with a previous vascular history. The use of pegylated interferon, imatinib, and JAK2 inhibitors is currently being evaluated.