Myelodysplastic syndromes (MDS) are a diverse group of hematopoietic disorders characterized by dysplasia, peripheral cytopenias, and risk of progression to acute myeloid leukemia and death. In patients who are ineligible for potentially curative hematopoietic stem cell transplantation (HSCT), approved therapies such as lenalidomide, azacitidine, and decitabine are available for those who previously would have received supportive care alone. Each treatment can achieve hematologic improvement and enhance quality of life. Azacitidine is the only treatment to show a significant survival advantage in patients with higher-risk MDS compared with conventional care regimens. The treatment panorama has been further enhanced with immunosuppressive agents, growth factor support, and biologic response modifiers. Initial treatment decisions are based around HSCT eligibility and when best supportive care becomes insufficient. Transfusion dependence is associated with adverse outcomes and is an indication for possible treatment escalation.