Significant advances have been made in the diagnosis and management of patients with polycythemia vera (PV) over the past two decades, but a few important issues remain, either overlooked or controversial. We discuss making an accurate diagnosis of PV with careful interpretation of hematocrit values, red cell count, and red cell mass when available, and bone marrow histomorphology to distinguish PV from other JAK2 myeloproliferative neoplasms (MPNs). We cover aspects of initial PV treatment with phlebotomy (PHL), its drawbacks in the long term, and alternative strategies. We comprehensively discuss cytoreductive therapy using interferon-alpha or hydroxyurea, with emphasis on patient selection, treatment goals, clinical endpoints, biomarkers and, most importantly, event-free and overall survival. A bone marrow biopsy in PV is essential for diagnosis and baseline histomorphology. Both hematocrit and red cell counts should be controlled with both phlebotomy (PHL) and cytoreductive agents. PHL alone is often inadequate in the long term, and cytoreduction is needed for most. Interferon is our preferred first-line agent due to improved survival outcomes. Short-term biomarkers predictive of long-term outcomes are needed to guide optimal therapy and development of new treatments.