Polycythemia vera (PV) is currently classified by the World Health Organization (WHO) classification system under the major category of myeloproliferative neoplasms (MPN)1 . Although the WHO MPN category includes seven subcategories, the term “MPN” usually refers to the three JAK2 mutation-enriched clinicopathologic entities: PV, essential thrombocythemia (ET) and primary myelofibrosis (PMF)1 . PV and its sister diseases constitute stem cell-derived clonal myeloproliferation that is characterized by three mutually-exclusive “driver” mutations: JAK2, CALR, and MPL, with respective distribution frequency of ~99, 0, and 0% for PV, 55, 22, and 3% for ET and 65, 20 and 7% for PMF2 . The most frequent MPN-associated JAK2 mutation is the exon 14 JAK2V617F, which is responsible for almost all the JAK2 mutations in ET and PMF, and 97% of those seen in PV; the remainder 3% of JAK2 mutations in PV are spread across exons 12, 13, and 143,4 . Diagnosis of PV often requires the presence of a JAK2 mutation, in addition to documentation of increased hemoglobin/hematocrit, to a threshold level established by the 2016 World Health Organization (WHO) revised criteria (>16.5 g/dL/49% for males and >16 g/dL/48% for females)1 . In addition, bone marrow morphologic assessment is encouraged, in order to distinguish PV from JAK2-mutated ET5-7 and obtain cytogenetic information, which has recently been shown to be prognostically relevant8–۱۰٫ Clinical features in PV include mild-tomoderate degree of splenomegaly, mild-to-moderate degree of constitutional symptoms, including fatigue and pruritus, symptoms of hyperviscosity, leukocytosis, thrombocytosis, microvascular symptoms (e.g., headaches, lightheadedness, visual disturbances, atypical chest pain, erythromelalgia, paresthesia), thrombotic and bleeding complications, and risk of leukemic transformation or fibrotic progression11. Current treatment in PV has not affected the natural history of the disease in regards to overall, leukemia-free or myelofibrosis-free survival, but thrombosis-free survival has been positively affected by treatment with phlebotomy12, aspirin13 and cytoreductive drugs11. In the latter regard, the most popular and evidence-supported cytoreductive agent is hydroxyurea, while busulfan has been effectively and safely utilized for an even longer period11,14. More recently, interferon (IFN)-α and ruxolutinib (a JAK1 and JAK2 inhibitor) have been introduced to the therapeutic armamentarium, without controlled evidence of superiority over the older drugs and documentation of safety during long-term use. In the current review, we provide a risk-adapted treatment algorithm in PV, including critical assessment of the currently available cytoreductive agents.