Mounting evidence indicates that the presence of measurable ("minimal") residual disease (MRD), defined as posttherapy persistence of leukemic cells at levels below morphologic detection, is a strong, independent prognostic marker of increased risk of relapse and shorter survival in patients with acute myeloid leukemia (AML) and can be used to refine risk-stratification and treatment response assessment. Because of the association between MRD and relapse risk, it has been postulated that testing for MRD posttreatment may help guide postremission treatment strategies by identifying high-risk patients who might benefit from preemptive treatment. This strategy, which remains to be formally tested, may be particularly attractive with availability of agents that could be used to specifically eradicate MRD. This review examines current methods of MRD detection, challenges to adopting MRD testing in routine clinical practice, and recent recommendations for MRD testing in AML issued by the European LeukemiaNet MRD Working Party. Inclusion of MRD as an end point in future randomized clinical trials will provide the data needed to move toward standardizing MRD assays and may provide a more accurate assessment of therapeutic efficacy than current morphologic measures.