A longstanding endeavor to define the genetic lesions that drive myeloid malignances has stimulated a period of remarkable discovery. Enabled by technological advances that have sharply decreased the cost of DNA sequencing, the full compendium of common, recurrent somatic mutations in the coding genome of myeloid malignancies is nearly complete. As the focus of genetic discovery shifts to the non-coding genome, renewed attention is being applied to the clinical and biological implications of recent genomic advances. Although the potential for this newfound knowledge to influence the care of patients has not yet been realized, broad genetic surveys of patient samples are now being employed to improve the accuracy of disease diagnosis, to define a molecular taxonomy of myeloid malignancies, to refine prognostic and predictive models, and to identify novel therapeutic strategies. Here, we will review recent advances in the genetics of myeloid malignancies and discuss their potential impact on clinical practice.