Minimal (measurable) residual disease (MRD) in acute leukemia denotes the presence of leukemic cells detected by multiparameter flow cytometry or various molecular techniques in patients achieving hematological remission. The MRD become an independent, post-diagnosis, prognostic indicator important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis in acute myeloid leukemia (AML). However, several issues remain with regard to the ideal time point to measure MRD, the clinically significant threshold, the sample (peripheral blood or bone marrow) should be used, and the standardize tests, so that results from different laboratories become comparable. This review gives an overview of the currently available evidence regarding technical issues, prognostic impact, and MRD-directed treatment for AML.