Colorectal cancer is the third most deadly cancer in the United States. Due to advances in chemotherapeutic agents, metastasectomy, and the development of drugs such as monoclonal antibodies targeting the angiogenic and epidermal growth factor receptor pathways, colorectal cancer has become one of the most advanced tumors in the world in terms of efficacy in the last 20 years (ranked fourth). Prior to 2000, fluorouracil-based therapies had been the leading treatment for stage III (lymph node-positive) and stage IV (metastatic) colorectal cancer. In the 12 years since then, however, new effective treatments have emerged, with chemotherapeutic agents and targeted drugs performing well in this type of disease. Irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, and ziv-aflibercept all prolonged overall survival in stage IV patients. However, only oxaliplatin can be used as an adjuvant therapy after surgery and provide a survival benefit in stage III patients. Many well-designed, methodologically sound studies have found that the population of patients with stage III colon cancer after surgical resection does not benefit in survival from treatment with irinotecan, bevacizumab, and more recently, cetuximab. This strongly predicts that the efficacy of treatment for metastatic tumors is not equivalent to that of adjuvant therapy. Therefore, the need to select additional effective adjuvant therapies for patients with stage III colorectal cancer who have undergone surgical resection but may still have metastases present faces a number of difficulties. In 2009, Chan et al. reported that regular aspirin administration after diagnosis of colorectal cancer reduced overall mortality by 21% and colorectal cancer-specific mortality by 29% in a prospective study that included 1239 patients diagnosed with stage I, II, or III colorectal cancer. Subgroup analysis showed that the reduction in overall and colorectal cancer-specific mortality with aspirin occurred only in patients whose primary tumors overexpressed prostaglandin-peroxidase 2 (PTGS2, formerly known as cyclooxygenase 2), a rate-limiting enzyme that converts arachidonic acid to prostaglandins. Recently, these controversial findings were confirmed and expanded by an analysis of a large retrospective study from the Netherlands that included 4481 patients diagnosed with colorectal cancer and observed a 23% reduction in overall mortality among those who continued to take or started taking aspirin after diagnosis compared to those who did not take aspirin, similar to that described previously. Our current understanding of the anti-cancer effects of aspirin is enriched by a meta-analysis study from the United Kingdom that included 17,285 patients and included five randomized studies evaluating daily aspirin use for the prevention of cardiovascular events. They found that aspirin reduced the risk of fatal adenocarcinoma by 35% and the risk of metastatic adenocarcinoma by 31%, and reduced the risk of metastasis by 74% in the current and follow-up periods. Thus, fairly compelling epidemiologic evidence suggests that aspirin use reduces progression and recurrence of colorectal cancer.