Fedratinib has a role in both JAK-inhibitor naive intermediate-/high-risk myelofibrosis patients and in patients that have previously received ruxolitinib. It has recently received FDA approval for these indications as well. Momelotinib does not appear to have an advantage over ruxolitinib with regards to improving splenomegaly in intermediate-/high-risk JAK-inhibitor naive myelofibrosis. However, increased rates of transfusion independence have been noted with momelotinib. Pacritinib has been studied in myelofibrosis patients with significant baseline anemia and thrombocytopenia; these trials support the use of pacritinib in myelofibrosis patients with significant thrombocytopenia. While ruxolitinib is effective in reducing the symptom burden and splenomegaly of patients with myeloproliferative neoplasms, a majority of patients will ultimately progress on therapy. Newer-generation JAK inhibitors including fedratinib, momelotinib, and pacritinib are being prospectively evaluated to determine their appropriate roles in the management of myeloproliferative neoplasms. In addition, both combination therapies with JAK inhibitors and novel investigational therapies are being actively explored.