Ever since their description as "myeloproliferative syndromes" by William Dameshek in 1951, the myeloproliferative neoplasms (MPNs) have been managed by the selective use of rather mundane, nonspecific therapies that rely on either antiplatelet effects or myelosuppression. The year 2005 ushered in a new era of drug development and discovery for the MPNs after the description of the JAK2 V617F mutation and the role this constitutively active tyrosine kinase has in MPN pathogenesis. Subsequently, multiple pharmacologic agents have begun (or are about to begin) testing for the inhibition of JAK2 in an attempt to improve the treatment of MPNs. Both primary myelofibrosis and myelofibrosis following essential thrombocythemia or polycythemia vera have been the targets of the most extensive testing of these agents to date. Responses to these oral JAK2 inhibitors have been primarily intended to reduce splenomegaly and meaningfully improve symptoms; effects on the JAK2 V617F allele burden or marrow histology are limited. Toxicities have ranged from myelosuppression to significant diarrhea. Additional agents with other mechanisms of action are also targeting JAK2, including histone deacetylase inhibitors and mTOR inhibitors. The results of preliminary trials of JAK2 inhibitors in polycythemia vera and essential thrombocythemia have been mixed but are premature. Many questions remain as to the optimal JAK2 inhibitory strategy and the full extent of the benefit of single-agent JAK2 inhibition.