The mechanisms underlying hematopoietic stem cell or progenitor cell abnormalities in myelodysplastic syndromes (MDSs) remain poorly characterized. Current evidence exists for multiple intrinsic and extrinsic influences upon the stem cell in these disorders. These influences are outlined in this review and include: stem cell characteristics in MDSs, as compared with those in acute myelogenous leukemia; the role of increased apoptosis; the role of signaling pathway abnormalities; the influences of immune modulation; and the effect of stromal cells and stromal cell cytokine production. Despite numerous studies that have examined these factors, how they converge to produce a situation in which accelerated proliferation and accelerated death occur simultaneously remains largely an unexplored area. It is anticipated that future studies that focus on well-characterized and purified progenitor populations in these disorders will elucidate the process by which ineffective hematopoiesis results from the influences of stem cell abnormalities versus abnormalities in the stem cell's microenvironmental and immunologic milieu.