Colorectal cancer (CRC) is the second most common cancer globally and one of the deadliest human malignancies. Traditional therapies, such as surgery, chemotherapy, and combination therapies have been used to treat patients with CRC. However, recently immunotherapy has been considered a practical and attractive therapeutic approach in various cancers, such as CRC. Among the immunotherapy methods, chimeric antigen receptor (CAR)-T, and CAR-natural killer cells (NK) cells therapy have been significantly successful, mainly in treating hematological malignancies. However, the effectiveness of CAR-T/NK cell therapy in the treatment of solid tumors, such as CRC has been less than blood malignancies due to various challenges, such as the selection of tumor antigens, lack of proper trafficking in tumor tissue, immunosuppressive tumor microenvironment, tumor heterogeneity and, adverse effects during and after CAR-T/NK cell therapy. This review summarized the biological structure of CAR-T/NK cells and their use in various types of human malignancies, particularly CRC, as well as the challenges of this type of treatment and the outcome of related combination therapies.