Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and despite cure rates exceeding 90% in children, it remains an important cause of morbidity and mortality in children and adults. The past decade has been marked by extraordinary advances into the genetic basis of leukemogenesis and treatment responsiveness in ALL. Both B-cell and T-cell ALL comprise multiple subtypes harboring distinct constellations of somatic structural DNA rearrangements and sequence mutations that commonly perturb lymphoid development, cytokine receptors, kinase and Ras signaling, tumor suppression, and chromatin modification. Recent studies have helped to understand the genetic basis of clonal evolution and relapse and the role of inherited genetic variants in leukemogenesis. Many of these findings are of clinical importance, and ongoing studies implementing clinical sequencing in the management of leukemia are expected to improve diagnosis, monitoring of residual disease, and early detection of relapse and to guide precise therapies. Here, we provide a concise review of genomic studies in ALL and discuss the role of genomic testing in clinical management.