Chimeric antigen receptor (CAR) T cell therapies for leukemia (e.g. tisagenlecleucel) and lymphoma (e.g. axicabtagene ciloleucel) have recently received regulatory approval in the United States. Phase I/II trials have demonstrated complete remission of refractory or relapsed tumors in 50% - 94% patients. However, the clinical successes of engineered T cells for the treatment of solid malignancies have thus far been few and far between. Furthermore, several instances of severe and lethal toxicities have arisen due to on-target, off-tumor recognition of antigen by T cell products. Recent advances in phase I trials for solid tumors, as well as in pre-clinical models, have revealed several variables that will be important to consider for the successful use of CAR-T cells in treating solid tumors. These variables include (i) regional versus systemic delivery; (ii) scFv versus ligand interactions; (iii) antigen loss versus escape; (iv) epitope spreading and (v) checkpoint expression on immune cells or tumor cells. Also, there remains outstanding mechanistic questions related to why differences exist in the persistence and tonic signaling of second-generation CD28 versus 4-1BB co-stimulated CAR-T cells. In addition, we are now learning the roles of lympho-depleting regimens (and associated toxicities) in modifying the persistence of engineered T cell therapies. A more comprehensive view of CAR-T cell strategies and important advances, both of pre-clinical and clinical evaluations, in solid tumors is necessary to drive these therapies forward.