Patients with advanced forms of primary myelofibrosis (PMF) have an average survival of 4 to 5 years. At present, the standard of care for these patients is largely palliative, including supportive measures and the use of a variety of therapeutic agents, each of which's directed toward reducing transfusion requirements or decreasing the degree of splenomegaly. Currently, allogeneic stem-cell transplantation remains the only potentially curative approach for PMF. Although the administration of Janus Kinase 2 (JAK2) inhibitors to patients with PMF often dramatically reduces the degree of splenomegaly and improves in systemic symptoms, these drugs do not correct the cytopenias associated with PMF, nor do they reverse abnormalities of BM architecture or substantially influence the JAK2V617F allele burden. Furthermore, the effects of such small-molecule therapy on the natural history of PMF and the rate of its evolution to acute myeloid leukemia (AML) remain uncertain. Recently, additional genetic alterations that precede or accompany JAK2V617F in PMF have been documented. These findings indicate that therapies directed against a single genetic lesion such as JAK2V617F are unlikely to be curative of PMF. These observations have led us to consider alternative therapeutic targets for drug development. The dysregulation of the hematopoietic microenvironment in PMF provides an attractive therapeutic target. Novel agents capable of correcting the abnormalities seen in PMF would probably be used in combination with the currently available therapeutic armamentarium, including the JAK2 inhibitors, to treat patients with PMF, which would represent a paradigm shift in the management of such patients.