Abstract The era of genomic medicine has allowed acute myeloid leukemia (AML) researchers to improve disease characterization, optimize risk-stratification systems, and develop new treatments. Although there has been significant progress, AML remains a lethal cancer because of its remarkably complex and plastic cellular architecture. This degree of heterogeneity continues to pose a major challenge, because it limits the ability to identify and therefore eradicate the cells responsible for leukemogenesis and treatment failure. In recent years, the field of single-cell genomics has led to unprecedented strides in the ability to characterize cellular heterogeneity, and it holds promise for the study of AML. In this review, we highlight advancements in single-cell technologies, outline important shortcomings in our understanding of AML biology and clinical management, and discuss how single-cell genomics can address these shortcomings as well as provide unique opportunities in basic and translational AML research.