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Simple Summary: Chimeric antigen receptors (CARs) targeting CD19 have emerged as a new treatment for hematological malignancies. As a "living therapy", CARs can precisely target and eliminate tumors while proliferating inside the patient's body. Various preclinical and clinical studies are ongoing to identify potential CAR-T cell targets for acute myeloid leukemia (AML). We shed light on the continuing efforts of CAR development to overcome tumor escape, exhaustion, and toxicities. Furthermore, we summarize the recent progress of a range of putative targets exploring this unmet need to treat AML. Lastly, we discuss the advances in preclinical models that built the foundation for ongoing clinical trials. Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML). [ABSTRACT FROM AUTHOR]