Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms with an annual incidence of 4.1 cases per 100,000 Americans. Patients with MDS suffer from chronic cytopenias that may lead to recurrent transfusions, infections, and increased risk for bleeding. They are also at risk for progression to acute myeloid leukemia. Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for MDS, although 3 drugs have been approved by the US Food and Drug Administration for its treatment: lenalidomide, 5-azacitidine, and decitabine. These therapies can be effective in the relief of cytopenias, achievement of cytogenetic remissions, and reduction in bone marrow blasts. 5-azacitidine has also been shown to improve overall survival. However, there remain many unmet needs in the treatment of MDS. Breakthroughs in our understanding of the complex pathogenesis of MDS through epigenetic, genetic, immunologic, and other biological mechanisms have allowed us to develop new therapeutic strategies that can lead to improvements in outcomes in MDS. In this review, we aim to provide an overview of the evolution in classifcation and risk stratifcation in MDS and to illustrate how we can use this to guide us in tailoring therapeutic choices in this disease. Responses and outcomes related to com monly used MDS therapies will be discussed together with novel therapies that have evolved with the improved understanding of MDS pathophysiology.