An increasingly complete compendium of recurrently mutated genes in myelodysplastic syndromes (MDS) has been defined, and the application of massively parallel sequencing to identify mutations in clinical practice now promises to improve the care of patients with this disease. More than 25 recurrent MDS-associated somatic mutations have been identified, involving biologic pathways as diverse as chromatin remodeling and pre-mRNA splicing. Several of these mutations have been shown to have prognostic implications that are independent of existing risk stratification systems based on clinical and pathologic parameters. Application of these recent discoveries to diagnosis, prognosis, risk stratification, and treatment selection for patients with MDS has the potential to improve patient outcomes. Here, we review recent advances in MDS and discuss potential applications of these discoveries to clinical practice.