Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, debilitating constitutional symptoms and bone marrow failure. Disease-related anemia is common and associated with an inferior quality of life and survival. Unfortunately, few therapies exist to improve hemoglobin in myelofibrosis patients. Momelotinib is a JAK1/JAK2 inhibitor that also antagonizes ACVR1, leading to downregulation of hepcidin expression and increased availability of iron for erythropoiesis. In clinical testing, momelotinib has demonstrated a unique ability to improve hemoglobin and reduce transfusion burden in myelofibrosis patients with baseline anemia, while producing reductions in spleen size and symptom burden. This review explores the preclinical rationale, clinical trial data and future role of momelotinib in the evolving therapeutic landscape of myelofibrosis. Plain language summary Patients with myelofibrosis (MF), a blood cancer, experience many symptoms including tiredness, night sweats and an increased spleen size. They also may experience low red blood cell counts (anemia) and require blood transfusions. MF is normally treated with medications called JAK inhibitors, but they worsen anemia. Momelotinib is a new JAK inhibitor that may be able to improve anemia. This is a review article that covers the available information on momelotinib and describes how this new drug may be incorporated into the future treatment of MF.