TP53 is a key tumor suppressor gene that plays an important role in regulating apoptosis, senescence, and DNA damage repair in response to cellular stress. Although somewhat rare, TP53-mutated AML has been identified as an important molecular subgroup with a prognosis that is arguably the worst of any. Survival beyond one year is rare after induction chemotherapy with or without consolidative allogeneic stem cell transplant. Although response rates have been improved with hypomethylating agents, outcomes remain particularly poor due to short response duration. Improvements in our understanding of AML genetics and biology have led to a surge in novel treatment options, though the clinical applicability of these agents in TP53-mutated disease remains largely unknown. This review will focus on the epidemiology, molecular characteristics, and clinical significance of TP53 mutations in AML as well as emerging treatment options that are currently being studied.