The use of minimal residual disease (MRD) measurement as a "surrogate" marker of molecular response to treatment, can potentially improve the evaluation of treatment response and enable estimates of the residual leukemic cell burden during clinical remission, thereby improving the selection of therapeutic strategies and, possibly, long-term clinical outcome. The most specific and sensitive methods for MRD monitoring currently available are polymerase chain reaction amplification of fusion transcripts and rearranged immunoglobulin or antigen-receptor genes, and flow cytometric detection of aberrant immunophenotypes. Several retrospective studies in childhood acute lymphoid leukemias (ALL) have used one of the different approaches for the detection of MRD. The strong association between MRD and risk of relapse was observed in children and adult patients irrespective of the methodology used. The promising results on the predictivity of MRD evaluation at the end of induction treatment has challenged the need for a new definition of remission. There is now urgent need to incorporate MRD data in clinical studies, properly designed to address treatment questions. In this context, several ongoing cooperative study groups have adopted a MRD-based risk group classification to explore whether a better tailored treatment would result in further improvement in cure rates for children with ALL.