Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2(V617F)), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2(V617). Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10-25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated.