The watershed discovery of the JAK2V617F mutation in 2005, and the high prevalence of this mutation in the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), has led to a renaissance in the science and therapy of these disorders. Inhibitors of JAK2 entered clinical trials in 2007 and ushered in an unprecedented era of trials with agents specifically designed for MPNs. Currently 10 different JAK2 inhibitors have been tested in myelofibrosis (MF) with varying degrees of specificity for the JAK2 kinase. In MF these agents have shown near universal ability to decrease pathologic splenomegaly and improve disease-associated symptoms. However, the ability of these agents to significantly impact disease-associated cytopenias, JAK2 allele burden, or bone marrow histologic features remains unclear. JAK2 inhibition in polycythemia vera (PV) and essential thrombocythemia (ET) for this class of agents appears promising to reduce myeloproliferations, symptoms, and perhaps prevent thrombohemorrhagic events. Alternative agents (with alternative targets), used either alone or in combination, might perhaps further augment the spectrum of efficacy and therapeutic options for MPNs.