Acute myeloid leukemia (AML) is a genetically heterogeneous disease that, even with current advancements in therapy, continues to have a poor prognosis. Recurrent somatic mutations have been identified in a core set of pathogenic genes including FLT3 (25-30% prevalence), NPM1 (25-30%), DNMT3A (25-30%), IDH1/2 (5-15%), and TET2 (5-15%), with direct diagnostic, prognostic, and targeted therapeutic implications. Advances in the understanding of the complex mechanisms of AML leukemogenesis have led to the development and recent US Food and Drug Administration (FDA) approval of several targeted therapies: midostaurin and gilteritinib targeting activated FLT3, and ivosidenib and enasidenib targeting mutated IDH1/2. Several additional drug candidates targeting other recurrently mutated gene pathways in AML are also being actively developed. Furthermore, outside of the realm of predicting responses to targeted therapies, many other mutated genes, which comprise the so-called long tail of oncogenic drivers in AML, have been shown to provide clinically useful diagnostic and prognostic information for AML patients. Many of these recurrently mutated genes have also been shown to be excellent biomarkers for post-treatment minimal residual disease (MRD) monitoring for assessing treatment response and predicting future relapse. In addition, the identification of germline mutations in a set of genes predisposing to myeloid malignancies may directly inform treatment decisions (particularly stem cell transplantation) and impact other family members. Recent advances in sequencing technology have made it practically and economically feasible to evaluate many genes simultaneously using next-generation sequencing (NGS). Mutation screening with NGS panels has been recommended by national and international professional guidelines as the standard of care for AML patients. NGS-based detection of the heterogeneous genes commonly mutated in AML has practical clinical utility for disease diagnosis, prognosis, prediction of targeted therapy response, and MRD monitoring.