Until recently, our understanding of the genetic factors contributing to the pathogenesis of acute lymphoblastic leukemia (ALL) has relied on the detection of gross chromosomal alterations and mutational analysis of individual genes. Although these approaches have identified many important abnormalities, they have been unable to identify the full repertoire of genetic alterations in ALL. The advent of high-resolution, microarray-based techniques to identify DNA copy number alterations and loss-of-heterozygosity in a genome-wide fashion has enabled the identification of multiple novel genetic alterations targeting key cellular pathways, including lymphoid differentiation, cell cycle, tumor suppression, apoptosis and drug responsiveness. Recent studies have extended these approaches to examine the biologic basis of high-risk ALL and treatment relapse. As these techniques continue to evolve and are integrated with genome-wide epigenetic and transcriptomic data, we will obtain a comprehensive understanding of the genetic and epigenetic alterations in ALL, and ultimately will be able to translate these findings into the development of novel therapeutic approaches directed against rational therapeutic targets. Here, we review recent data obtained from genome-wide profiling studies in ALL, and discuss potential avenues for future investigation.