Simple SummaryMyelofibrosis is an aggressive bone marrow cancer whose clinical presentation can be extremely heterogenous. Two distinct phenotypes, myeloproliferative and myelodepletive or cytopenic, have increasingly been recognized in recent years. The two phenotypes represent the two ends of the disease spectrum and are characterized by opposing trends for a wide range of clinical variables (e.g., peripheral blood counts, spleen volume) and molecular profiles that result in significantly different prognoses and outcomes. The myeloproliferative phenotype is usually associated with normal/higher peripheral blood counts and larger spleen volume, higher mutantJAK2allele burden, fewer “non-driver mutations”, and superior overall survival. The myelodepletive phenotype is associated with progressive anemia and/or thrombocytopenia, modest splenomegaly, more high molecular risk mutations, lower mutantJAK2allele burden, and inferior outcomes. Management of myelofibrosis is largely dictated by clinical needs, including the degrees of splenomegaly, symptoms and cytopenias, as well as prognostic risk assessment. Ruxolitinib and fedratinib are more efficacious in the myeloproliferative phenotype, whereas momelotinib and pacrtitinib can address the unmet needs of the myelodepletive phenotype.AbstractMyelofibrosis (MF) presents an array of clinical manifestations and molecular profiles. The two distinct phenotypes− myeloproliferative and myelodepletive or cytopenic− are situated at the two poles of the disease spectrum and are largely defined by different degrees of cytopenias, splenomegaly, and distinct molecular profiles. The myeloproliferative phenotype is characterized by normal/higher peripheral blood counts or mildly decreased hemoglobin, progressive splenomegaly, and constitutional symptoms. The myeloproliferative phenotype is typically associated with secondary MF, higherJAK2V617F burden, fewer mutations, and superior overall survival (OS). The myelodepletive phenotype is usually associated with primary MF, ≥2 cytopenias, modest splenomegaly, lowerJAK2V617F burden, higher fibrosis, greater genomic complexity, and inferior OS. Cytopenias are associated with mutations in epigenetic regulators/splicing factors, clonal evolution, disease progression, and shorter OS. Clinical variables, in conjunction with the molecular profiles, inform integrated prognostication and disease management. Ruxolitinib/fedratinib and pacritinib/momelotinib may be more suitable to treat patients with the myeloproliferative and myelodepletive phenotypes, respectively. Appreciation of MF heterogeneity and two distinct phenotypes, the different clinical manifestations and molecular profiles associated with each phenotype alongside the growing treatment expertise, the development of non-myelosuppressive JAK inhibitors, and integrated prognostication are leading to a new era in patient management. Physicians can increasingly tailor personalized treatments that will address the unique unmet needs of MF patients, including those presenting with the myelodepletive phenotype, to elicit optimal outcomes and extended OS across the disease spectrum.