The myelodysplastic syndrome(s) (MDS), bone marrow stem cell malignancies that share pathogenetic overlap with acute myeloid leukemia, are characterized by peripheral blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest. Premature apoptosis of bone marrow cellular elements contributes to ineffective hematopoiesis, which is exacerbated by stromal production of inflammatory cytokines. Abrogation of the effects of these cytokines represents an area of active clinical research, particularly in the treatment of low-risk MDS. In high-risk MDS, the activation of oncogenes and the inactivation of tumor suppressor genes predominate over inhibitory cytokines as proliferation predominates over apoptosis. Agents such as thalidomide, lenalidomide and the hypomethylating drugs 5-azacytidine and decitabine have shown promising efficacy and tolerability in clinical trials, and may represent a springboard for future treatment combinations.