In acute myeloid leukemia (AML) that is in complete remission, minimal residual disease (MRD) is presumed to be present, though not morphologically evident. Advances in diagnostics now permit the detection and quantification of MRD in AML by several techniques. The level of MRD after induction and consolidation therapy correlates with disease sensitivity to chemotherapy and has greater power to predict long-term survival than patient and disease characteristics that are available at diagnosis, including genetic information. A unique advantage of MRD is that it is an integrated measure of the impact and interaction of genetics, epigenetics, host immune milieu, bone marrow environment, and drug sensitivity on disease response to treatment. Here, we review the main techniques for MRD assessment in AML, including polymerase chain reaction, multiparameter flow cytometry, and next-generation sequencing, with a focus on method-specific and general limitations to the optimal employment of MRD techniques for the determination of AML prognosis. We also review the data that establish the prognostic and predictive value of MRD assessment in AML. Finally, we provide recommendations for the use of MRD in the care of patients with AML in clinical practice today, including whether it should influence treatment decisions.