Regular exercise has been shown to improve control of lipid abnormalities, diabetes mellitus, hypertension, and obesity, with the greatest benefits realized by sedentary individuals who begin to exercise. Responses to exercise interventions are often highly variable among individuals, however, and research has indicated that response to exercise may be mediated in large part by variation in genes. As we strive to unravel the complex etiology of diseases like obesity, diabetes, and cardiovascular disease through the use of molecular and genetic tools now available, understanding the interaction and influence of environmental factors, such as exercise, on gene expression and function has taken on increasing importance. This review briefly summarizes strategies presently being used to elucidate genes and genetic effects that may be mediated or influenced by exercise and serves to illustrate the importance of considering the effect of exercise when investigating genes related to health or other physiological outcomes.