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With current treatment regimens, event-free survival rates for childhood acute lymphoblastic leukemia (ALL) approach or exceed 80%. This success was achieved, in part, through the implementation of risk-stratified therapy. However, for the 15–20% of children with newly diagnosed ALL who will ultimately relapse, traditional risk assessment remains inadequate. This review highlights recent advances in our understanding of prognostic factors that may be used to refine risk group classification.An increasingly sophisticated understanding of genetic abnormalities in leukemia cells (including chromosomal abnormalities and patterns of gene expression), response to treatment, and host pharmacogenomics offers the potential to enhance or supplant currently applied prognostic criteria for use in treatment planning for childhood ALL.Identification of biologically distinctive subsets of ALL through cytogenetic, molecular, and gene expression studies, as well as investigations of minimal residual disease and host pharmacogenomics, offer promising avenues of research. Integration of molecular tools into clinical practice will ultimately allow for more precise risk stratification and individualized treatment planning.