Chimeric antigen receptors (CARs) have achieved promising results in treating B-cell malignancies and multiple myeloma, and led to the approval by the FDA of multiple autologous CAR T cell products. CARs allow T-cells to target any antigen of choice, independent of MHC expression. However, there are challenges to extending the use of CAR T cells to solid tumors and other pathologies. Progress in CAR design, cell manufacturing, and genome editing hold the promise of generating safer and more effective genetically instructed immunity. Novel engineered cell types, including innate T-cell types, natural killer cells, macrophages, and induced pluripotent stem cell-derived immune cells, are on the horizon, as are applications of CAR T cells to treat autoimmunity and other pathologies.