There has been a remarkable explosion of knowledge into the molecular defects that underlie the acute and chronic leukemias, leading to the introduction of targeted therapies that can block key cellular events essential for the viability of the leukemic cell. Our understanding of the pathogenesis of the myelodysplastic syndromes (MDSs) has lagged behind, at least in part, because they represent a more heterogeneous group of disorders. The significant immunologic abnormalities described in this disease, coupled with the admixture of MDS stem or progenitor cells within the myriad types of dysplastic and normal cells in the bone marrow and peripheral blood, have made it difficult to molecularly characterize and model MDS. The recent availability of several, effective (ie, FDA-approved) therapies for MDS and newly described mouse models that mimic aspects of the human disease provide an opportune moment to try to leverage this new knowledge into a better understanding of and better therapies for MDS.