Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, accounting for almost 30% of pediatric cancers. Despite the high rate of cure, ALL is one of the leading causes of death in children with tumor. For this reason, there is a keen interest in identifying genetic and biological features that influence the pathogenesis of ALL and the risk of treatment failure. The application of standard diagnostic technologies such as a conventional karyotype and polymerase chain reaction methodologies, together with gene expression profiling and genome-wide analyses, allows us to genetically characterize almost 100% of children with ALL. This review provides basic information about well-established genetic alterations associated with specific clinical subtypes and new molecular lesions with potential prognostic impact. New insights are reported on the natural history of ALL. Genetic aberrations in childhood ALL are considered both markers of disease and potential targets of treatment. Here, each biological subtype under the genetic point of view has been dissected, including genes involved in the development of lymphocytes and considerations on ALL in infancy. It is also crucial to discuss the issue of relapse. Finally, as future treatment will be individualized on the basis of biological features, the pediatric hemato-oncologists need to be ready and prepared to tailor the “right treatment” to the “right children” with ALL.