The detection of minimal residual disease (MRD) in patients with acute leukemia has been studied for about 15 years by different groups in both the United States and Europe. It has been found that MRD detection can be performed using molecular and immunophenotypic aberrancies that are present in the leukemic clone at diagnosis and not in normal bone marrow. When performing MRD assessments after chemotherapy, it is possible to identify patients at risk for relapse. This review is not an overview of all MRD studies, but rather discusses the possibilities for optimizing MRD detection, the use of flow cytometry versus polymerase chain reaction techniques, and the implications for future patient treatment. When informative, we compare literature on MRD in acute myeloid leukemia (AML) with information from MRD studies in acute lymphoblastic leukemia. Finally, we address the promising detection of AML stem cells, the likely cells of origin in AML, for prediction of clinical outcome and guidance of future therapies.