Two highly sensitive methods, multiparameter flow cytometry (MFC) and real‐time quantitative PCR (RQ‐PCR), are increasingly used to monitor minimal residual disease (MRD) and to guide risk‐adapted management in acute myeloid leukemia (AML). An independent prognostic impact has been demonstrated for MRD levels obtained by both methods. MFC has been found particularly useful for assessment of early clearance of malignant cells and after consolidation therapy. At the latter checkpoint, MRD levels quantified by RQ‐PCR in AML with fusion genes also have the strongest prognostic power. In addition, highly predictive initial expression levels have been identified by RQ‐PCR. Both methods are capable of early detection of relapse. Through the use of all available markers including NPM1 mutations and FLT3 mutations in addition to fusion genes, RQ‐PCR‐based MRD assessment is possible in more than half of patients, whereas MFC is applicable to most AML cases. With a sensitivity of 10⁻⁴ (PML‐RARA) to 10⁻⁷ (patient‐specific primers, FLT3 and NPM1 mutations), RQ‐PCR is more sensitive in most cases. Large clinical trials will determine the exact role and place of immunologic and RQ‐PCR‐based monitoring of MRD in the therapy of patients with AML. Cancer 2008. © 2007 American Cancer Society.