From its beginnings two decades ago with the analysis of chromosomal translocation breakpoints, research into the molecular pathogenesis of acute lymphoblastic leukemia (ALL) has now progressed to the large-scale resequencing of candidate oncogenes and tumor suppressor genes in the genomes of ALL cases blocked at various developmental stages within the B- and T-cell lineages. In this review, we summarize the findings of these investigations and highlight how this information is being integrated into multistep mutagenesis cascades that impact specific signal transduction pathways and synergistically lead to leukemic transformation. Because of these advances, fueled by improved technology for mutational analysis and the development of small-molecule drugs and monoclonal antibodies, the future is bright for a new generation of targeted therapies. Best illustrated by the successful introduction of imatinib mesylate, these new treatments will interfere with disordered molecular pathways specific for the leukemic cells, and thus should exhibit much less toxicity and fewer long-term adverse effects than currently available therapeutic modalities.