Understanding how genes, environment, and personal motivation operate to influence physical activity will require (i) inclusion of properly validated measures of putative mediators (e.g., cultural values, efficacy and control beliefs, goals, intentions, enjoyment, and self-management skills) and moderators (e.g., age or maturation, personality, race/ethnicity, fitness, fatness, skill, and competing behaviors) of physical activity, (ii) a search for candidate genes involved with motivational systems of energy expenditure in addition to energy intake pathways, (iii) assessment of specific features physical activity exposure (i.e., type, intensity, timing, and context), (iv) manipulation of physical activity or prospective observation of change in physical activity at multiple times, rather than cross-sectional association and linkage studies, and (v) use of statistical procedures that permit multilevel modeling (i.e., personal and group-level variables) of direct, indirect (i.e., mediated), and moderated (i.e., interactions of mediators with external factors) relations with physical activity within theoretical gene–environment networks.