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Colorectal cancer is a major worldwide health care problem that accounts for 1 million new cases each year. The risk factors for this disease include hereditary factors, environmental agents, and inflammatory stimuli that affect the gastrointestinal tract. Among these risk factors, cyclooxygenase-2 (COX-2) is one of the major players in the progression of colorectal cancer; however, the detailed mechanism of its role in causing colorectal cancer is still not well understood. In addition, the role of COX-2 signaling through the interaction in the epithelial and stromal compartments on colorectal carcinogenesis has not been fully illustrated. In the present review, we provide published evidence to demonstrate that (1) COX-2 signaling plays a major role in the progression of colorectal cancer, (2) activation of COX-2 in the stromal compartment also contributes to colorectal carcinogenesis, and (3) inhibition of COX-2 signaling by COX-2 inhibitors might be an effective method to control colorectal cancer. We have also summarized recent advances and insights from mechanistic studies of colorectal cancer to help prevent and control this deadly disease and provide our opinion regarding the importance of risk reduction and disease prevention for colorectal cancer.