Acute leukemia is the commonest childhood cancer and a major cause of morbidity from hematologic malignancies in adults. Acute lymphoblastic leukemia (ALL) is commonest in children, and acute myeloid leukemia (AML) is more frequent in adults. Apart from childhood ALL, the prognosis of acute leukemia is suboptimal, with many patients experiencing relapse, which carries a poor prognosis, or toxicities from nonspecific therapies. Recent years have witnessed great interest in the application of high-resolution, genome wide approaches to the study of acute leukemia. These studies have identified multiple novel genetic alterations targeting critical cellular pathways that contribute to leukemogenesis, including alterations of genes regulating lymphoid development, tumor suppressors, apoptosis regulators, and oncogenes. These studies have also delineated novel genetic alterations that are associated with prognosis, and have demonstrated substantial evolution in patterns of genetic alterations from diagnosis to relapse, indicating that specific genetic changes determine resistance to therapy in ALL. Overall, fewer recurring alterations have been identified in AML. These studies have demonstrated the power of genome-wide approaches to identify new lesions in acute leukemia, and suggest that ongoing genomic analyses, including deep resequencing and epigenetic analysis, will continue to yield novel, clinically relevant insights into the pathogenesis of this disease.