Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematological and solid malignancies. However, despite the success of this field, there remain some major challenges, including accelerated T cell exhaustion, potential toxicities, and insertional oncogenesis. To overcome these limitations, recent advances in CRISPR technology have enabled targetable interventions of endogenous genes in human CAR T cells. These CRISPR genome editing approaches have unleashed the therapeutic potential of CAR T cell therapy. Here, we summarize the potential benefits, safety concerns, and difficulties in the generation of gene-edited CAR T cells using CRISPR technology.