Epidemiological evidence has revealed an inverse relationship such that increased physical activity as measured directly subjective recall, job classification, former athletic status, or indirectly by physical fitness is associated with decreased incidence and (or) mortality rates for various cancers. The relationship appears strongest for colon cancer and female estrogen-dependent cancers of the breast, ovary, and endometrium. While some epidemiological studies have controlled for numerous confounding variables such as smoking, body mass index, and percent body fat, it is still difficult to ascertain whether physical activity exerts an independent effect on cancer above and beyond that associated with an improved lifestyle and numerous other potential confounding variables. Experimental studies performed in animals suggests that chronic exercise, especially when performed prior to tumorigenesis, can retard, delay, or prevent the incidence, progression, or spread of experimental tumors. There is also limited animal evidence suggesting that exercise may help ameliorate cancer cachexia. Exercise or physical activity may contribute to a reduction in site-specific cancers by different physiological mechanisms. Some purported mechanisms include decreased lifetime exposure to estrogen or other hormones, reduced body fat, enhanced gut motility, improved anti-oxidant defenses, and stimulation of anti-tumor immune defenses. Unfortunately, most animal studies have failed to account for plausible biological mechanisms as to how exercise might influence cancer. In addition, the exercise or activity dosage required to provide optimal protection from cancer is unclear. Interpretation of epidemiological studies is hampered by the numerous and sometimes inaccurate assessments of physical activity. Likewise, many animal studies have utilized unrealistic exercise protocols. Clearly, more research is needed to define appropriate activity or exercise dosages definitively and to explore the mechanism(s) by which exercise helps protect against cancer. Nevertheless, moderate exercise appears to be a safe and effective means of aiding in the prevention of cancer and should be adopted by the public in addition to other prudent behavioral practices such as proper diet. More research needs to be performed regarding the effects of exercise or physical activity on those who already have cancer to determine if exercise improves their prognosis.