Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow disorders characterized by both bone marrow failure and a propensity for development of acute myeloid leukemia. The incidence of these conditions has risen sharply over the past several years, making them the most common malignant bone marrow disorders. While the majority of patients are diagnosed with low-grade disease, approximately two-thirds will succumb to complications of peripheral blood cytopenias or progression to acute leukemia. In recent years, there has been striking progress in our understanding of the pathogenesis of these disorders. For example, the recognition of the roles of angiogenesis and cytokine abnormalities in the development of these diseases led to clinical trials with agents such as thalidomide, which yielded encouraging erythroid responses. Subsequent work with the thalidomide derivative lenalidomide resulted in marked erythroid and cytogenetic responses in individuals with the 5q- abnormality. Additionally, the identification of hypermethylation as an important aspect in the pathogenesis of these and other hematological diseases led to clinical trials utilizing the demethylating agents azacitidine and decitibine. These agents are now known to result in trilineage responses in 30% to 50% of patients with MDS with as many as 20% achieving partial or complete remissions. These results have altered the natural history of these diseases in a significant number of patients. Investigators anticipate that further studies with tyrosine kinase, histone deacetylase, and farnesyl transferase inhibitors will contribute to already promising attempts to reverse or block the pathogenesis of these diseases. Other novel agents are being evaluated as investigators continue to make progress for patients affected by these disorders.