Myelodysplastic syndromes (MDS) include a diverse group of clonal hematopoietic disorders characterized by progressive cytopenias and propensity for leukemic progression. The biologic heterogeneity that underlies MDS translates clinically in wide variations of clinical outcomes. Several prognostic schemes were developed to predict the natural course of MDS, counsel patients, and allow evidence-based, risk-adaptive implementation of therapeutic strategies. The prognostic schemes divide patients into subgroups with similar prognosis, but the extent to which the prognostic prediction applies to any individual patient is more variable. None of these instruments was designed to predict the clinical benefit in relation to any specific MDS therapy. The prognostic impact of molecular mutations is being more recognized and attempts at incorporating it into the current prognostic schemes are ongoing.