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MF is a multifaceted disease characterized by trilineage myeloid proliferation with prominent megakaryocyte atypia and bone marrow fibrosis, as well as splenomegaly, constitutional symptoms, ineffective erythropoiesis, extramedullary hematopoiesis, and a risk of leukemic progression and shortened survival. Therapy can range from observation alone in lower\u2010risk and asymptomatic patients to allogeneic hematopoietic stem cell transplantation, which is the only potentially curative treatment capable of prolonging survival, although burdened by significant morbidity and mortality. The discovery of the\n                    <jats:italic>JAK2<\/jats:italic>\n                    V617F mutation prompted the development of JAK inhibitors (JAKi) including the first\u2010in\u2010class JAK1\/JAK2 inhibitor ruxolitinib and subsequent approval of fedratinib, pacritinib, and momelotinib. The latter has shown erythropoietic benefits by suppressing hepcidin expression via activin A receptor type 1 (ACVR1) inhibition, as well as reducing splenomegaly and symptoms. However, the current JAKi behave as anti\u2010inflammatory drugs without a major impact on survival or disease progression. A better understanding of the genetics, mechanisms of fibrosis, cytopenia, and the role of inflammatory cytokines has led to the development of numerous therapeutic agents that target epigenetic regulation, signaling, telomerase, cell cycle, and apoptosis, nuclear export, and pro\u2010fibrotic cytokines. Selective JAK2 V617F inhibitors and targeting of mutant CALR by immunotherapy are the most intriguing and promising approaches. This review focuses on approved and experimental treatments for MF, highlighting their biological background.\n                  <\/jats:p>","DOI":"10.1002\/ajh.27658","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T12:54:36Z","timestamp":1741611276000},"page":"30-50","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Targeted Therapies in Myelofibrosis: Present Landscape, Ongoing Studies, and Future Perspectives"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6241-1206","authenticated-orcid":false,"given":"Giuseppe G.","family":"Loscocco","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero\u2010\u00a0Universitaria Careggi University of Florence  Florence Italy"},{"name":"Division of Hematology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Guglielmelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero\u2010\u00a0Universitaria Careggi University of Florence  Florence 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