This concise review focuses on the most recent advances in understanding molecular genetic abnormalities in childhood acute leukemia (ALL). An increasing number of chromosomal translocations associated to distinct molecular genetic abnormalities have been described. Recurrent motifs have been recognized behind the great heterogeneity of genes involved in chromosomal translocations occurring in childhood ALL. The expression or activation of specific genes encoding for transcription factors have been recognized to be the most frequent recurring mechanism. In addition to the identification of genes involved in translocations, the analysis of deleted or mutated genes has provided new insights into the molecular pathogenesis of childhood ALL. The understanding of the genetic heterogeneity has turned out to have great impact on routine diagnosis and treatment. Molecular analysis has revealed that the t(12;21) translocation, barely detectable when searched for by conventional cytogenetic techniques, is the most frequent genetic lesion occurring in childhood ALL. Accumulating evidence clearly indicates that molecular characterisation at diagnosis represents the most relevant prognostic information for risk stratification of the patients at diagnosis. Several target genes are now available for the study of minimal residual disease and to evaluate its potential impact for tailoring treatment. Finally, our progress in understanding the relationships between genetic lesions and environmental etiologic agents will further contribute to delineating the natural history of pediatric ALL.