In this panel discussion from the 7th International Workshop on Acute Leukemias, Eunice Wang, MD, Roswell Park Comprehensive Cancer Center, Buffalo, NY; Andrew Wei, MBBS, PhD, Peter MacCallum Cancer Centre & Royal Melbourne Hospital, Melbourne, Australia; David Sallman, MD, Moffitt Cancer Center, Tampa, FL; and Gabriel Mannis, MD, Stanford University, Stanford, CA, examine the difficult biology and poor prognosis associated with TP53-mutated acute myeloid leukemia, noting that traditional therapies often yield limited benefit. They explore novel therapeutic avenues under investigation, such as TP53 reactivators, STING agonists, tagraxofusp, and arsenic-based treatments, aiming to improve outcomes in this high-risk subgroup.