Human obesity is the result of both environmental and genetic factors. In this manuscript, we briefly review the metabolic factors predicting body weight gain in Pima Indians, a population prone to obesity. The metabolic predictors of weight gain are: 1) a low metabolic rate, 2) low levels of physical activity, 3) low rates of fat oxidation, 4) insulin sensitivity, 5) low sympathetic nervous system activity, and 6) low plasma leptin concentrations. In contrast, obesity is associated with high metabolic rate, high fat oxidation, low insulin sensitivity and high plasma leptin concentration. This observation emphasizes the need to conduct prospective studies to obtain a better understanding of the etiology of obesity. In addition, genetic studies will help to identify new pathways involved in the pathophysiology of obesity.