Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a variable propensity for leukemic transformation. In recent years there has been an explosion of information on the molecular genetic changes underlying these disorders. This information has substantial prognostic implications, and the influence on therapeutic approaches and the treatment of patients is evolving. Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only known cure for these diseases, but appropriate patient selection is of utmost importance from a risk-benefit perspective. This review focuses on the factors influencing risk stratification in MDS and optimal choice of front-line therapy in the current era, including the interplay of clinical factors and molecular genetic factors, and factors that determine eligibility for alloSCT. The myelodysplastic/myeloproliferative diseases also will be discussed, including the increasing effort to understand the molecular genetics and natural history of these disorders and treatment approaches.