Achieving long-term control of colorectal cancers with therapeutic vaccines that generate potent anti-tumor T cell and antibody responses has been a goal for more than two decades. To date, clinical trials of these vaccines have demonstrated induction of immune responses, but clinical benefit has been limited. Improved vector delivery systems with enhanced immunostimulatory properties, decreased immunogenicity against vector and improved antigen presentation are some of the key features of modern tumor vaccines. Furthermore, an improved understanding of the various immunosuppressive factors in the tumor microenvironment and regional lymph nodes, coupled with a burgeoning ability to impair inhibitory immune synapses, highlights a growing opportunity to induce beneficial antigen-specific responses against tumor. The combination of improved antigenic delivery systems, coupled with therapeutic immune activation, represents state-of-the-art colorectal vaccine design concepts with the goal of augmenting immune responses against tumor and improving clinical outcomes.