Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy that is often associated with relapse and drug resistance after standard chemotherapy or targeted therapy, particularly in older patients. Hematopoietic stem cell transplants are looked upon as the ultimate salvage option with curative intent. Adoptive cell therapy using chimeric antigen receptors (CAR) has shown promise in B cell malignancies and is now being investigated in AML. Initial clinical trials have been disappointing in AML, and we review current strategies to improve efficacy for CAR approaches. The extensive number of clinical trials targeting different antigens likely reflects the genetic heterogeneity of AML. The limited number of patients reported in multiple early clinical studies makes it difficult to draw conclusions about CAR safety, but it does suggest that the efficacy of this approach in AML lags behind the success observed in B cell malignancies. There is a clear need not only to improve CAR design but also to identify targets in AML that show limited expression in normal myeloid lineage cells.