The diagnosis and risk stratification of acute myeloid leukemia (AML) primarily rely on morphologic analysis and assessment of karyotype by chromosome banding analysis. For decades, standard AML induction therapy has utilized the combination of anthracyclines and cytarabine. Despite the use of postremission therapy, less than half of patients with AML will be cured of their disease. Allogeneic hematopoietic stem cell transplantation combines cytoreductive chemotherapy with adoptive immunotherapy and may cure patients who fail chemotherapy alone. Recent advances in next-generation sequencing have yielded important insights into the molecular landscape of AML with normal karyotype. Integrated prognostic models incorporating somatic mutation analyses may outperform prediction based on conventional clinical and cytogenetic factors alone. We review the evolution of risk profiling of AML from the cytogenetic to molecular era and describe the implications for AML diagnosis and postremission therapy. Expected final online publication date for the Annual Review of Medicine Volume 67 is January 14, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.