Current chemotherapeutic regimens achieve CR in a large percentage of patients with AML. However, relapse after CR remains a significant problem. The presence of leukemic cells at levels too low to be detected by conventional microscopy, termed minimal residual disease (MRD), has been associated with an increased risk of relapse and shortened survival. Detection of MRD requires the use of highly sensitive ancillary techniques. Multi-color flow cytometric immunophenotyping is a sensitive method for quick and accurate detection of MRD. Use of this method in patient management may result in lower rates of relapse and improved survival, and is an effective means of assessing novel therapeutic agents. This method can be used in the vast majority of patients with AML, regardless of the immunophenotypic, cytogenetic and molecular genetic abnormalities present. Unfortunately, conflicting data regarding optimum methods of measurement and reporting, as well as the expertize required to interpret results have limited broad application of this technique. We provide a broad overview of this technique, including its advantages and limitations, and discuss the methods employed at our institution. We also review several possible areas of future investigation.