The unprecedented success of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib in myelofibrosis (MF) provided much-needed impetus for clinical drug development for the Philadelphia chromosome–negative myeloproliferative neoplasms. The survival benefit conferred by this agent, along with its marked efficacy with regard to spleen volume and symptom reduction, have made ruxolitinib the cornerstone of drug therapy in MF. However, there remain significant unmet needs in the treatment of patients with MF, and many novel classes of agents continue to be investigated in efforts to build on the progress made with ruxolitinib. These include inhibitors of histone deacetylases (HDACs) and DNA methyltransferases, phosphatidylinositol-3-kinase isoforms, heat shock protein 90, cyclin-dependent kinases 4/6, and Hedgehog signaling, among others. In parallel, other JAK inhibitors with potential for less myelosuppression or even improvement of anemia, greater selectivity for JAK1 or JAK2, and the ability to overcome JAK inhibitor persistence are in various stages of development. First-in-class agents such as the activin receptor IIA ligand trap sotatercept (for anemia of MF), the telomerase inhibitor imetelstat, and the antifibrotic agent PRM-151 (recombinant human pentraxin-2) are also in clinical trials. In polycythemia vera, a novel interferon administered every 2 weeks is being developed for front-line therapy in high-risk individuals, and inhibitors of human double minute 2 (HDM2) have shown promise in preclinical studies, as have HDAC inhibitors such as givinostat (both in the laboratory and in the clinic). Ruxolitinib is approved for second-line therapy of polycythemia vera and is being developed for essential thrombocythemia.