Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (i.e. not yet molecularly defined) myeloproliferative disorder (MPD), along with essential thrombocythemia (ET) and polycythemia vera (PV). All three MPDs represent stem-cell-derived clonal myeloproliferation that, in the case of MMM, is accompanied by an intense bone marrow stromal reaction that includes collagen fibrosis, osteosclerosis, and angiogenesis. To date, both the molecular basis of the primary clonal process and the pathogenetic mechanisms that underlie the secondary histological changes remain elusive. Clinically, MMM is characterized by anemia, multi-organ extramedullary hematopoiesis that often involves the spleen and liver, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Current diagnosis is based on characteristic but not diagnostic bone marrow histological features. Modern therapy remains palliative but allogeneic stem cell transplantation might be curative to a selected group of patients. This chapter reviews both the old and the new therapy with regard to non-transplant treatment options for MMM.