Although surgery remains the only curative option for patients with gastrointestinal (GI) malignancies, the use of adjuvant chemotherapy and/or localized radiation is considered standard therapy for patients who present with locoregional disease. Even with adjuvant therapy, however, the 5-year survival rate for such patients ranges from 2% to 50%, depending on the specific cancer type and stage. As a result, more effective interventions are necessary for all but the earliest stages of GI malignancies. Colon cancer represents the paradigm for the management of GI malignancies, not only because it is, by far, the most common cancer in this group, but also because the biological progression to disease is well characterized. Immunotherapy is an alternative approach for treating GI malignancies that can either: (1) activate tumor-specific T-cells; or (2) use monoclonal antibodies derived from tumor-specific antigens. Monoclonal antibodies act by a mechanism that is distinct from that of chemotherapy and, thus, represent a non-cross-resistant treatment with an entirely different spectrum of toxicities. Thanks to an improved understanding of tumor immunology, as well as the events needed to generate an optimal immune response, the possibility of designing an effective colon cancer vaccine approach that induces both humoral and cellular responses has become even more realistic.