Chimeric antigen receptor T (CAR-T) cell therapy has drawn increasing attention over the last few decades given its remarkable effectiveness and breakthroughs in treating B cell hematological malignancies. Even though CAR-T cell therapy has outstanding clinical successes, most treated patients still relapse after infusion. CARs are derived from the T cell receptor (TCR) complex and co-stimulatory molecules associated with T cell activation; however, the similarities and differences between CARs and endogenous TCRs regarding their sensitivity, signaling pathway, killing mechanisms, and performance are still not fully understood. In this review, we discuss the parallel comparisons between CARs and TCRs from various aspects and how these current findings might provide novel insights and contribute to improvement of CAR-T cell therapy efficacy.