Abstract Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder associated with an average survival of less than 5 years. Therapy for PMF has used chemotherapeutic agents, immunomodulatory drugs, or biological-response modifiers that have not always been directed at the biological processes that underlie the origins of PMF. Such strategies are palliative and have an uncertain effect on survival. At present, allogeneic stem cell transplantation (ASCT) is the only means of altering the natural history of patients with PMF and provides the only hope for cure of this disorder. Enthusiasm for ASCT in PMF has been muted due to an unacceptable transplantation-related morbidity and mortality in patients receiving fully myeloablative conditioning regimens. Recently, a variety of reduced-intensity conditioning regimens have been utilized in older patients with PMF with significant comorbidities with promising results. Greater understanding of the cellular and molecular events that lead to the development of PMF have provided the opportunity for targeted therapies for PMF. Such therapies must be first evaluated in phase 1/2 trials using a variety of endpoints to assess their efficacy and their potential associated toxicities. The performance of randomized clinical trials comparing these agents to the present standard of care would permit for the first time evidence-based therapeutic decisions to be made for patients with PMF.