Several techniques developed in recent years provide us with the capability to detect sub-microscopic leukemia during remission. Quantitative polymerase chain reaction (PCR) is thus far the most sensitive assay that is applicable in most patients with acute lymphoblastic leukemia (ALL) of childhood. However, false-positive and false-negative results may provide the clinician with misleading data and therefore PCR analysis should be accompanied by another assay and changes in the level of residual disease should be confirmed at different time points following treatment. Furthermore, several studies did not determine a threshold of residual disease level above which relapse is likely to occur, and more recent data show that long-term remission may be sustained in the presence of residual disease. Thus, additional studies of the biology of residual disease in childhood ALL should be performed before sensitive assays of residual disease detection and quantitation can be clinically utilized.