There have been significant improvements in the diagnosis and treatment of colorectal cancer over the past 15 years. However, some 30% of patients with colorectal cancer have disseminated disease at presentation, and furthermore, 50% of patients initially believed to be cured by surgery subsequently relapse and die of the disease. Novel treatment concepts based on understanding the molecular signatures that separate tumor from normal epithelium, such as immunotherapy, are aimed at abolishing microscopic residual disease post standard treatment. The authors provide an overview of progress in the development of specific and nonspecific immunotherapies and explain why definition of end-points and early translation of immunotherapy into the adjuvant field are key to effective use of such agents in the clinical setting.