The presence of minimal residual disease (MRD) in the bone marrow (BM) of patients with acute myeloid leukemia (AML) following chemotherapy has been established by many studies to be strongly associated with relapse of leukemia. In addition, detection of MRD is the major objective of many of the newer diagnostic techniques used in malignant hematology. Because of the wide availability and conceptual straightforwardness of immunophenotyping, flow cytometry is the most accessible method for MRD detection. This review is not an overview of all MRD studies, but rather discusses the possibilities for optimizing MRD detection, the use of multiparameter flow cytometry (MFC) techniques in MRD detection, and the implications for future patient treatment. This review focuses on MRD detection in AML using MFC and discusses the reported correlations of MRD, clinical and biologic features of the disease, and outcome. In addition, it discusses the laboratory and clinical aspects of this approach.