The BCR-ABL-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Historically, complex biochemical alterations defining these heterogeneously distinct malignancies have remained elusive and constrained available therapy options. The discovery of Janus kinase (JAK) mutations collectively present in BCR-ABL-negative MPNs has led to a resurgence of medical interest in JAK-STAT targeted treatment modalities, as well as provided a unique platform for inhibiting symptom-directing proinflammatory cytokines. INCB018424, CYT387, SB1518, and TG101348 are among the most propitious JAK2 inhibitors under investigation, providing substantial improvement in constitutional symptoms, transfusion-dependent cytopenias, and reduction in spleen size. Despite their attributes, evidence of complete or partial remission has yet to be observed with therapy. Many uncertainties surrounding the full clinical potential of JAK2 inhibitors persist. Treatment guidelines addressing optimal stages for drug implementation, ideal dosing parameters and criteria for medication continuation/withdrawal may effectively resolve these ongoing concerns and provide advancements in the morbidity and mortality of these multifaceted disease processes.