Researchers studying acute myeloid leukemia (AML) have been able to better characterize the disease, improve risk-stratification methods, and create new treatments thanks to the era of genomic medicine. Despite major advancements, AML’s extremely intricate and plastic cellular architecture means that it is still a fatal malignancy. Because it makes it difficult to pinpoint and then eliminate the cells that cause leukemogenesis and therapy failure, this level of heterogeneity continues to be a significant obstacle. Single-cell genomics has made unheard-of advancements in the study of cellular heterogeneity in recent years, and it shows promise for the investigation of AML.