Chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in chemorefractory B cell malignancies, raising the possibilities of using this immunotherapeutic modality for other devastating hematologic malignancies, such as acute myeloid leukemia (AML). AML is an aggressive hematologic malignancy which, like B cell malignancies, poses several challenges for clinical translation of successful immunotherapy. The antigenic heterogeneity of AML results in a list of potential targets that CAR-T cells could be directed towards, each with advantages and disadvantages. In this review, we provide an up-to-date report of outcomes and adverse effects from published and presented clinical trials of CAR-T cell therapy for AML and provide the preclinical rationale underlying these studies and antigen selection. Comparison across trials is difficult, yet themes emerge with respect to appropriate antigen selection and association of adverse effects with outcomes. We highlight currently active clinical trials and the potential improvements and caveats with these novel approaches. Key hurdles to the successful introduction of CAR-T cell therapy for the treatment of AML include the effect of antigenic heterogeneity and trade-offs between therapy specificity and sensitivity; on-target off-tumor toxicities; the AML tumor microenvironment; and practical considerations for future trials that should be addressed to enable successful CAR-T cell therapy for AML.