Assessing the level of residual disease in leukemia is vital for evaluating patients’ response to treatment and for identifying those at high risk of relapse. This should enable early preemptive intervention to prevent the onset of hematological relapse in those patients. One of the most common translocations in acute myeloid leukemia (AML) is the t(8;21). t(8;21) AML is characterized by a relatively good prognosis. This chapter discusses both qualitative and quantitative (real-time quantitative reverse-transcription polymerase chain reaction [RQ-PCR]) protocols for the diagnosis and minimal residual disease (MRD) monitoring in t(8;21) AML. It also discusses the importance of choosing appropriate controls for each assay. The chapter provides a simple equation for assessing the sensitivity/reliability of RQ-PCR assays, which enables scientists to assess the accuracy and reliability of their data.