Myelodysplastic syndromes (MDS) represent a clonal hematopoietic stem cell disorder characterized by morphologic features of dyspoiesis, a hyperproliferative bone marrow, and one or more peripheral blood cytopenias. In patients classified according to the Revised International Prognostic Scoring System (R-IPSS) with intermediate or higher-risk disease, there is an increased risk of death due to progressive bone marrow failure or transformation to acute myeloid leukemia (AML). Azacitidine was the first DNA hypomethylating agent approved by the United States (US) Food and Drug Administration (FDA) for the treatment of MDS and the only therapy that has demonstrated a significant survival benefit over conventional care regimens (CCRs) in patients with intermediate or higher-risk disease. Prolonged survival is independent of achieving a complete remission. Azacitidine has been used in older patients with both clinical and hematological improvement as well as an acceptable side effect profile. The most common adverse effect is myelosuppression. These findings support the use of azacitidine as an effective treatment in older patients with higher-risk MDS.