Submorphologic (ie, minimal) residual disease (MRD) can be monitored in virtually all children and adolescents with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) using methods such as flow cytometric detection of leukemic immunophenotypes or polymerase chain reaction amplification of fusion transcripts, gene mutations, and clonal rearrangements of antigen-receptor genes. Numerous studies have demonstrated the clinical importance of measuring MRD, spurring the design of clinical trials in which MRD is used for risk assignment and treatment selection. Emerging results from these trials suggest that the adverse prognostic impact of low levels of MRD during the early phases of therapy can be diminished by treatment intensification. This article discusses the methods used for detecting MRD in childhood AML and ALL, the data obtained in studies correlating MRD with treatment outcome, the results of the initial trials using MRD, and the practical aspects related to the design of MRD-based clinical studies.