Although many mechanisms remain unclear, a large body of evidence indicates that several dietary and lifestyle factors are likely to have a major influence on the risk of colon cancer. Physical inactivity, excess body weight, and a central deposition of adiposity are consistent risk factors. Overconsumption of energy is likely to be one of the major contributors to the high rates of colon cancer in Western countries. Beyond their influence on energy balance, the independent role of specific macronutrients remain controversial. Red meat, processed meats, and perhaps refined carbohydrates contribute to risk. Recent evidence indicate that chronic hyperinsulinemia may increase risk of colon cancer. As insulin resistance and subsequent hyperinsulinemia is induced by excess energy intake and some aspects of the Western diet (e.g., saturated fats and refined carbohydrates), insulin may be a focus of factors influencing colon cancer risk. Recent evidence also points to a role of IGF-1, but our understanding of modifiable factors that influence levels of these is poor at present. Of note is that hyperinsulinemia increases free IGF-1 exposure [25]. High alcohol consumption, probably in combination with a diet low in some micronutrients such as folate and methionine, and smoking early in life are likely to increase risk of colon cancer. Recent epidemiologic studies have tended not to support a strong influence of fiber; instead, some micronutrients or phytochemicals in fiber-rich foods may be important. Folate is one such nutrient that has received attention lately and is being studied in randomized intervention trials. Agents with chemopreventive properties, such as aspirin and postmenopausal estrogens, have potential adverse effects so a careful consideration of the risk-benefit ratio is required before general recommendations can be made. Other NSAIDs with a potential for reduced toxicity, such as celecoxib, are currently being evaluated for efficacy and toxicity. The overwhelming evidence indicates that primary prevention of colon cancer is feasible. At least 70% of colon cancers may be preventable by moderate changes in diet and lifestyle [197]. Secondary prevention, through screening by sigmoidoscopy and colonoscopy, is also critically important to prevent mortality from colon cancer; however, many of the diet and lifestyle risk factors for colon cancers are the same for cardiovascular disease and for some other cancers, so focusing on the modifiable risk factors for colon cancer is likely to have many additional benefits beyond this cancer.