Cytoreductive therapies have traditionally been the standard treatment for older patients with polycythemia vera (PV) or those with a history of prior thrombosis. Hydroxyurea (HU) is the most frequently used cytoreductive agent in PV. However, approximately 24% of patients treated with HU will eventually develop resistance or intolerance and patients who fail HU have an increased risk of death, transformation to myelofibrosis or acute myeloid leukemia. Interferon-alpha has been used in younger PV patients and is capable of inducing a complete hematologic response and significant reductions, or even eradication, of JAK2 V617F mutation allele burdens in a small but notable subset of PV patients. The potential toxicities of interferon-alpha must be weighed against the disease control benefit in a case-by-case fashion. Recently JAK2 inhibitor, ruxolitinib, demonstrated significant improvement in controlling the hematocrit and splenomegaly versus best available therapy in patients with PV who failed or are intolerant to HU and currently is FDA-approved in this setting. In this review, we will discuss novel emerging therapies for PV with a special focus on the currently available and upcoming treatment options for patients who fail HU. (C) 2016 Elsevier Ireland Ltd. All rights reserved.