Over the past decade, there has been exponential growth in the number of genome sequencing studies performed across a spectrum of human diseases as sequencing technologies and analytic pipelines improve and costs decline. Pediatric hematologic malignancies have been no exception, with a multitude of next generation sequencing studies conducted on large cohorts of patients in recent years. These efforts have defined the mutational landscape of a number of leukemia subtypes and also identified germ-line genetic variants biologically and clinically relevant to pediatric leukemias. The findings have deepened our understanding of the biology of many childhood leukemias. Additionally, a number of recent discoveries may positively impact the care of pediatric leukemia patients through refinement of risk stratification, identification of targetable genetic lesions, and determination of risk for therapy-related toxicity. Although incredibly promising, many questions remain, including the biologic significance of identified genetic lesions and their clinical implications in the context of contemporary therapy. Importantly, the identification of germ-line mutations and variants with possible implications for members of the patient’s family raises challenging ethical questions. Here, we review emerging genomic data germane to pediatric hematologic malignancies.