Acute myeloid leukemia (AML) was one of the first cancers to be sequenced at the level of the whole genome. Molecular profiling of AML through targeted sequencing panels and cytogenetics has become a mainstay in risk-stratifying AML patients and guiding clinicians toward optimal therapies for their patients. The extensive high-resolution genomic data generated to characterize AML have been instrumental in revealing the tremendous biological complexity of the disease, dictated in part by mutational, clonal, and epigenetic heterogeneity. This is further complicated by the antecedent nonleukemic state of clonal hematopoiesis that nevertheless is associated with an increased risk of developing a hematologic malignancy and with a greater risk of mortality from ischemic cardiovascular disease. Here in this review, we discuss developments in the field of AML biology and therapeutics, with a focus on advances in our understanding of how genetic and epigenetic determinants of AML have influenced prognostication and recent shifts in treatment paradigms, particularly within the context of precision oncology, for this highly complex group of hematologic malignancies.