Peripheral blood lymphocytes can be engineered to express T-cell receptors (TCRs) that recognize human leukocyte antigen (HLA)-restricted cancer antigens and subsequently administered systemically as TCR-T cell therapy. A growing repertoire of tumor-exclusive antigens including cancer germline antigens, viral oncoproteins, and neoantigens has led to a broadening potential applicability of this targeted approach in patients with solid tumors. While TCR-T cell therapy has already demonstrated clinical efficacy in trials of patients with metastatic melanoma and certain sarcomas, it is now emerging as a promising investigational therapy for mismatch repair proficient epithelial cancers.