Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenia and by increased progression to acute myeloid leukemia (AML). Therapeutic interventions for MDS other than allogeneic stem cell transplantation have been palliative. Novel and targeted therapeutic agents such as the inhibition of farnesyltransferases and receptor tyrosine kinases, more potent thalidomide analogs, arsenic trioxide, immunomodulating agents, hypomethylating agents, and histone deacetylase inhibitors have shown encouraging results and may offer durable benefit to patients with MDS. Further development of rational therapies and improvements in the outcome of patients with MDS are likely to emerge from an increased understanding of the pathophysiology of these diseases.