Myelofibrosis with myeloid metaplasia (MMM) is a progressive, clonal, and lethal myeloproliferative disorder with a variable prognosis. The only potentially curative therapy for MMM is allogeneic stem cell transplantation, but this therapy is too toxic for older patients and inappropriate for young patients with good prognostic features. A nonmyeloablative or autologous stem cell transplant may broaden the applicability of high-dose therapy for MMM, but the therapy for MMM is palliative in intent and aimed at symptomatic relief. There is no approved therapy for MMM; however, certain agents have been useful for targeted palliation. Myelosuppressive drug therapy, targeted radiation, or splenectomy has decreased symptomatic myeloproliferation (i.e., splenomegaly). MMM-associated cytopenias may be improved by the selective use of growth factors, androgens, and thalidomide. Debilitating constitutional symptoms improve with the pharmacologic blockage of tumor necrosis factor-alpha. Further molecular understanding of MMM is necessary for more effective targeted therapies.