Colorectal cancer is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. While surgery remains the mainstay of therapy, approximately 50% of persons who undergo resection develop parenchymal metastatic disease. Unfortunately, current therapeutic regimens offer little improvement in survival. Using immunotherapy to fill this therapeutic gap has enjoyed limited success, reflecting a paucity of tumor-associated antigens. In that context, there is a significant unrealized opportunity to exploit structural and functional immune system compartmentalization to generate a therapeutic immune response against metastatic colorectal tumors employing biomarkers whose expression is normally confined to intestinal epithelial cells and their derivative malignancies. This novel class of biomarkers, here termed cancer mucosa antigens, may fill the unmet therapeutic need for colorectal cancer-associated immune targets. As a concrete example, guanylyl cyclase C is an intestinal mucosa-specific biomarker ideally suited to test this hypothesis and serve as the first cancer mucosa antigen for colorectal cancer immunotherapy. Here, we discuss colorectal cancer immunity, immune compartmentalization and preliminary results targeting guanylyl cyclase C in mouse models of colorectal cancer, as well as the potential paradigm shift to employing cancer mucosa antigens in immunotherapy of colorectal cancer.