Myelofibrosis with myeloid metaplasia (MMM) encompasses the diagnoses of agnogenic myeloid metaplasia (idiopathic myelofibrosis), as well as the advanced phases of polycythemia vera and essential thrombocythemia (post polycythemic and post thrombocythemia myeloid metaplasia, respectively). MMM is a clonal, hematopoietic stem cell disorder in which neither the pathogenesis, nor a broadly applicable effective therapy have been described. Clinically, these patients experience progressive marrow replacement by fibrotic tissue, ineffective hematopoiesis, problematic cytopenia's, significant hepato-splenomegaly, extramedullary hematopoiesis, profound constitutional symptoms, and a risk of blastic transformation. Historically, therapies have been targeted at palliating symptoms (i.e. splenectomy, transfusions, hydroxyurea, erythropoietin, androgens, localized radiotherapy). Stem cell transplantation appears promising, but is often toxic and not broadly applicable due to co-morbidities and age of MMM patients. Non-myeloablative approaches to conditioning may broaden the applicability of stem cell transplantation in MMM, yet results to date are preliminary. Although a definitive molecular abnormality responsible for the pathogenesis of MMM has not been described, much has been learned about the aberrant expression of pro-fibrotic cytokines and the presence of increased angiogenesis in MMM. These pathogenetic insights have led to a series of pilot clinical trials with therapeutic agents targeting aberrantly expressed cytokines (and possibly angiogenesis) including Thalidomide (alone or in combination), Etanercept, and STI-571. Amongst these later agents Thalidomide has demonstrated the most promise (palliating disease associated cytopenia's), whereas the TNF-alpha inhibitor Etanercept has aided with MMM associated constitutional symptoms. Although these later trials have been helpful in a subset of patients, no agent to date has led to solid complete responses in MMM across the spectrum of disease manifestations. Further insights into the pathogenetic mechanisms responsible for myeloproliferation (aberrant cell signaling pathways, apoptotic resistance, other) are necessary to guide selection and testing of the expanding number of novel anti-neoplastic agents in chronic myeloid disorders and MMM.