Chimeric antigen receptor (CAR) T-cell therapy against tumor antigens involves a recombinant immunoreceptor that combines an antibody-derived targeting fragment with signaling domains capable of activating T cells and fusion of this receptor domain to a costimulatory domain (typically CD28 or 4-1BB). Clinical trials of CAR T-cell therapeutics targeting CD19 antigens for relapsed or refractory B-cell malignancies have shown unparalleled results and consequently have recently been approved by the U.S. Food and Drug Administration. However, the lack of efficacy beyond B-cell malignancies, the emergence of resistance to CAR T-cell therapy due to loss of the antigenic epitope, and severe cases of cytokine release syndrome and neurotoxicity necessitate further preclinical studies. As it is very complicated to develop a single animal model that would replicate the complexity of the clinical scenario, this article focuses on transgenic models used to study human tumor-associated antigens in an immunocompetent model. © 2019 by John Wiley & Sons, Inc.