 Despite recent advances in cancer immunotherapy, only a minority of colorectal cancer patients can potentially benefit from immune checkpoint inhibitors highlighting an unmet need for improving survival in metastatic colorectal cancer, MCRC. Various approaches to manipulate patient immunity to recognize and kill colorectal cancer cells are being explored simultaneously, with combination therapies likely being the most effective. Ideally, therapies would target tumor-restricted antigen selectively found in tumors while overcoming cellular and molecular inhibitory pathways, self-tolerance, and T-cell exhaustion to mount an effective cytotoxic T-cell response and clinical benefit in patients with MCRC. This article was authored by Barbara Bashir and Adam E. Snooke.