Molecular, cellular, and epidemiologic findings suggest that neurohormonal, epigenetic, and microbiologic mechanisms may influence risk for obesity by interacting with socioenvironmental factors. Homeostatic and nonhomeostatic neural controls of energy predispose people to obesity, and this predisposition may be exaggerated by the influence of media, marketing, and sleep patterns. Epigenetic gene regulation may account for the influence of modifiable early life or maternal exposures on obesity risk. Alterations in gut flora caused by infant feeding practices or later diet may influence the absorption and storage of energy. Further exploration of how these molecular-cellular mechanisms might increase obesity risk in response to modifiable socioeconomic factors requires the partnership of laboratory and public health researchers.