Chimeric antigen receptor (CAR)-expressing T cells have demonstrated potent clinical efficacy in patients with B cell malignancies. However, the use of CAR-T cell therapy targeting other cancers has, in part, been limited by both the induction of antigen-specific toxicities targeting normal tissues expressing the target-antigen, and the extreme potency of CAR-T cell treatments resulting in life-threatening cytokine-release syndromes. Herein, we discuss toxicities associated with CAR-T cell therapy in the clinic. Further, we discuss potential clinical interventions to ameliorate these toxicities and the application of preclinical animal models to predict the clinical utility of CAR-T cell therapy.