Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and remains a main cause of death in children despite recent improvements in cure rates. In the past decade, development of massively parallel sequencing has enabled large scale genome profiling studies of ALL, which not only led to identification of new subtypes in both B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL), but has also identified potential new therapeutic approaches to target vulnerabilities of many subtypes. Several of these approaches have been validated in preclinical models and are now being formally evaluated in prospective clinical trials. In this review, we provide an overview of the recent advances in our knowledge of genomic bases of BCP-ALL, T-ALL, and relapsed ALL, and discuss their clinical implications.