In this fascinating discussion, John DiPersio, MD, PhD, Washington University School of Medicine, Saint Louis, MO, Saar Gill, MD, PhD, University of Pennsylvania, Philadelphia, PA, and Rizwan Romee, MD, Dana-Farber Cancer Institute, Boston, MA, discuss the major challenges to CAR-T therapy in acute myeloid leukemia (AML), highlighting recent work on strategies aiming to overcome these hurdles. Prof. DiPersio, Dr Romee, and Dr Gill start by outlining the benefits of CAR-natural killer (NK) therapy over CAR-T therapy, before exploring the best approaches to transduce NK cells. Moving forward, the experts discuss why some patients with AML may not respond to CAR-T therapy, highlighting the impact of T-cell fitness and cytokine release syndrome (CRS) on the success of immunotherapy. They also discuss novel treatment strategies including macrophage CARs for myelodysplastic syndromes (MDS) and targeting NPM1-mutated AML with anti-NPM1c CAR-NKs, and discuss the challenge of finding new target antigens in AML. This discussion took place at the 4th International Workshop on CAR-T (iwCAR-T) 2022 held in Tampa, FL.