Acquired genetic aberrations are the underlying cause of leukemogenesis in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The karyotypes of AML and ALL cases are generally quite simple as seen by chromosome banding analysis, with few genetic changes and a limited number of subclones. However, investigations using fluorescence in situ hybridization, loss of heterozygosity analysis, single-nucleotide polymorphism arrays, and, most recently, massively parallel sequencing have challenged this view. In particular, comparison of diagnostic and relapse samples, modeling in transgenic mice, and whole-exome and whole-genome sequencing have indicated that widespread genomic heterogeneity, which is masked by a dominant clone, may be present in AML and ALL. In the present review, our current knowledge of genomic heterogeneity in acute leukemia is summarized.