Ruxolitinib (INCB-018424) is a potent, orally available, selective inhibitor of both JAK1 and JAK2 of the JAK-STAT signaling pathway, being developed by Incyte Corp and Novartis AG. Ruxolitinib was initially developed to target the constitutive activation of the JAK-STAT pathway in patients with myeloproliferative neoplasms (MPNs). Meaningful reductions in spleen size and constitutional symptoms have been noted in patients with myelofibrosis (both primary and post-essential thrombocythemia/polycythemia vera). Data from a phase I/II clinical trial led to ongoing registration trials in the US and Europe. Toxicity (primarily decreased erythropoiesis and thrombocytopoiesis) has been managed by close control of dosing. The inhibition of inflammatory cytokine signaling through JAK1 inhibition has led to intriguing results in patients with rheumatoid arthritis and psoriasis (using a topical cream formulation). Ruxolitinib is a well tolerated, first-in-class JAK2 inhibitor with various potential clinical indications.