In the present review, we discuss the pathobiology of the BCL-2 family of proteins in <i>TP53</i>-mutated AML, mechanisms of venetoclax/BCL-2 inhibitor resistance in this molecular subset, and emerging strategies to potentially overcome this deficiency to guide therapeutic management for a population of patients who are in critical need of progress. This evidence concerns the gene TP53 and acute myeloid leukemia.