Adoptive cell therapy (ACT) is a highly personalized cancer treatment that involves the administration of immune cells with direct anticancer activity to cancer-bearing hosts. ACT using naturally occurring tumor-reactive lymphocytes has achieved durable, complete regressions in patients with melanoma, likely by targeting somatic mutations unique to each cancer. This approach has expanded to treat common epithelial cancers. Genetic engineering of lymphocytes to express conventional T cell receptors or chimeric antigen receptors (CARs) has further extended the application of ACT for cancer treatment. ACT offers several advantages over other forms of cancer immunotherapy, including the ability to grow large numbers of antitumor lymphocytes in vitro, select for high-avidity recognition of tumors, and manipulate the host to provide a favorable microenvironment for antitumor immunity. However, a major challenge is identifying cells that can target antigens selectively expressed on cancer cells but not essential normal tissues. ACT using Tumor-Infiltrating Lymphocytes (TILs) has shown significant efficacy in treating metastatic melanoma, with up to 55% of patients achieving objective responses. TILs can recognize cancer mutations, which may explain their antitumor activity. Genetic engineering of lymphocytes to express antitumor receptors, such as CARs, has broadened the application of ACT to other cancers. CARs can provide non-MHC-restricted recognition of cell surface components and are introduced into T cells with high efficiency using viral vectors. However, targeting antigens shared by tumors and normal tissues can lead to severe off-tumor, on-target toxicity. Efforts are ongoing to identify tissue-specific surface antigens expressed on essential normal tissues but not on solid tumors. The future of ACT for cancer treatment depends on identifying suitable targets for immunologic attack. While CARs have been successful in treating hematologic malignancies, their application to solid tumors is limited by the lack of suitable targets exclusive to cancer. Improving the specificity and function of T cells, optimizing lymphodepleting preparative regimens, and incorporating "suicide" genes for safety are among the strategies being explored to enhance ACT's effectiveness. Despite its complexity and cost, personalized ACT remains a promising approach for treating common epithelial cancers.Adoptive cell therapy (ACT) is a highly personalized cancer treatment that involves the administration of immune cells with direct anticancer activity to cancer-bearing hosts. ACT using naturally occurring tumor-reactive lymphocytes has achieved durable, complete regressions in patients with melanoma, likely by targeting somatic mutations unique to each cancer. This approach has expanded to treat common epithelial cancers. Genetic engineering of lymphocytes to express conventional T cell receptors or chimeric antigen receptors (CARs) has further extended the application of ACT for cancer treatment. ACT offers several advantages over other forms of cancer immunotherapy, including the ability to grow large numbers of antitumor lymphocytes in vitro, select for high-avidity recognition of tumors, and manipulate the host to provide a favorable microenvironment for antitumor immunity. However, a major challenge is identifying cells that can target antigens selectively expressed on cancer cells but not essential normal tissues. ACT using Tumor-Infiltrating Lymphocytes (TILs) has shown significant efficacy in treating metastatic melanoma, with up to 55% of patients achieving objective responses. TILs can recognize cancer mutations, which may explain their antitumor activity. Genetic engineering of lymphocytes to express antitumor receptors, such as CARs, has broadened the application of ACT to other cancers. CARs can provide non-MHC-restricted recognition of cell surface components and are introduced into T cells with high efficiency using viral vectors. However, targeting antigens shared by tumors and normal tissues can lead to severe off-tumor, on-target toxicity. Efforts are ongoing to identify tissue-specific surface antigens expressed on essential normal tissues but not on solid tumors. The future of ACT for cancer treatment depends on identifying suitable targets for immunologic attack. While CARs have been successful in treating hematologic malignancies, their application to solid tumors is limited by the lack of suitable targets exclusive to cancer. Improving the specificity and function of T cells, optimizing lymphodepleting preparative regimens, and incorporating "suicide" genes for safety are among the strategies being explored to enhance ACT's effectiveness. Despite its complexity and cost, personalized ACT remains a promising approach for treating common epithelial cancers.