Dysregulated JAK/STAT signaling underlies the pathogenesis of myelofibrosis, a myeloproliferative neoplasm characterized by cytopenias, splenomegaly and constitutional symptoms. JAK inhibitors, such as fedratinib, are the primary therapeutic option for patients with high-risk or symptomatic myelofibrosis. Fedratinib has characteristics that distinguish it from the other commercially available JAK inhibitors, such as its preferential inhibition of JAK2 and its inhibitory effects on kinases such as FLT3 and BRD4. Fedratinib is most often used in the second-line setting after intolerance or resistance to other JAK inhibitors, but there is substantial evidence that it is an effective first-line option in the appropriate patient population. Prevention and early treatment of fedratinib-related gastrointestinal toxicity is key to maintaining adequate drug exposure, and clinicians must remain vigilant for Wernicke encephalopathy during treatment. Fedratinib's JAK2 selectivity and kinome profile make it an appealing agent for alternative indications, such as myelodysplastic/myeloproliferative neoplasms and maintenance after bone marrow transplantation, which are under active investigation.