It is estimated that almost 1.5 million people in the USA are diagnosed with cancer every year. However, due to the substantial effect of modifiable lifestyle factors on the most prevalent cancers, it has been estimated that 50% of cancer is preventable. Physical activity, weight loss, and a reduction in alcohol use can strongly be recommended for the reduction of breast cancer risk. Similarly, weight loss, physical activity, and cessation of tobacco use are important behavior changes to reduce colorectal cancer risk, along with the potential benefit for the reduction of red meat consumption and the increase in folic acid intake. Smoking cessation is still the most important prevention intervention for reducing lung cancer risk, but recent evidence indicates that increasing physical activity may also be an important prevention intervention for this disease. The potential benefit of lifestyle change to reduce prostate cancer risk is growing, with recent evidence indicating the importance of a diet rich in tomato-based foods and weight loss. Also, in the cancers for which there are established lifestyle risk factors, such as physical inactivity for breast cancer and obesity for colorectal cancer, there is emerging information on the role that genetics plays in interacting with these factors, as well as the interaction of combinations of lifestyle factors. Integration of genetic information into lifestyle factors can help to clarify the causal relationships between lifestyle and genetic factors and assist in better identifying cancer risk, ultimately leading to better-informed choices about effective methods to enhance health and prevent cancer.