The myelodysplastic syndromes (MDSs) are common, acquired, clinically challenging hematologic conditions that are characterized by bone marrow failure and a risk of progression to acute leukemia. These disorders can arise de novo, especially in elderly patients or, less often, as a consequence of prior chemotherapy or radiotherapy for an unrelated disease. The MDS classification systems were revised recently and updated. These refined classification and prognostic schemes help stratify patients by their risk of leukemia progression and death; this knowledge can help clinicians select appropriate therapy. Although many treatments for MDS have been proposed and evaluated, at present, only hematopoietic stem cell transplantation offers any real hope for cure, and no available therapy beyond general supportive care offers benefit to more than a minority of patients. However, recent clinical trials enrolling patients with MDS have reported encouraging results with use of newer drugs, including lenalidomide, decitabine, and darbepoetin alfa. Other exciting treatment regimens are being tested. Here, we present a contemporary, practical clinical approach to the diagnosis and risk-stratified treatment of MDS. We review when to suspect MDS, detail how to evaluate patients who may have a form of the condition, explain key features of treatments that are currently available in the United States, and summarize a general, common-sense therapeutic approach to patients with MDS.