Simple SummaryAcute myeloid leukemia (AML) is a difficult-to-treat cancer, and chemotherapy can cause severe side effects. Patients may need stem cell transplantation, but this is challenging and not always successful. Even with intensive treatment, some patients may relapse or develop a refractory disease. Genetically modifying some white blood cells, called lymphocytes, with specific molecules called chimeric antigen receptors (CARs) can generate new therapies that can target AML. In this study, we gather all current data from the literature regarding the clinical testing of CAR-based therapies against AML. Moreover, we analyze the limitations of the most established therapy, CAR-T cells (T-lymphocytes with CARs). Additionally, we provide some insights into the potential benefits of using alternative lymphocytes, such as the CAR-NK cells (natural killer cells with CARs).AbstractAcute myeloid leukemia (AML) is a devastating disease. Intensive chemotherapy is the mainstay of treatment but results in debilitating toxicities. Moreover, many treated patients will eventually require hematopoietic stem cell transplantation (HSCT) for disease control, which is the only potentially curative but challenging option. Ultimately, a subset of patients will relapse or have refractory disease, posing a huge challenge to further therapeutic decisions. Targeted immunotherapies hold promise for relapsed/refractory (r/r) malignancies by directing the immune system against cancer. Chimeric antigen receptors (CARs) are important components of targeted immunotherapy. Indeed, CAR-T cells have achieved unprecedented success against r/r CD19+ malignancies. However, CAR-T cells have only achieved modest outcomes in clinical studies on r/r AML. Natural killer (NK) cells have innate anti-AML functionality and can be engineered with CARs to improve their antitumor response. CAR-NKs are associated with lower toxicities than CAR-T cells; however, their clinical efficacy against AML has not been extensively investigated. In this review, we cite the results from clinical studies of CAR-T cells in AML and describe their limitations and safety concerns. Moreover, we depict the clinical and preclinical landscape of CAR used in alternative immune cell platforms with a specific focus on CAR-NKs, providing insight into the future optimization of AML.