The cellular immunotherapy field has achieved important milestones in the last 30 years towards the treatment of a variety of cancers due to improvements in ex-vivo T cell manufacturing processes, the invention of synthetic T cell receptors, and advances in cellular engineering. Here, we discuss major preclinical models that have been useful for the validation of chimeric antigen receptor (CAR)-T cell therapies and also promising new models that will fuel future investigations towards success. However, multiple unanswered questions in the CAR-T cell field remain to be addressed that will require innovative preclinical models. Key challenges facing the field include premature immune rejection of universal CAR-T cells and the immune suppressive tumor microenvironment. Immune competent models that accurately recapitulate tumor heterogeneity, the hostile tumor microenvironment, and barriers to CAR-T cell homing, toxicity, and persistence are needed for further advancement of the field.