Nutritional genomics evaluates the effects of genetic variation in the interaction between diet and chronic diseases. The aim of this manuscript was to review the most important genetic polymorphisms associated with obesity, diabetes mellitus, and dietary factors. The main interactions among genetic polymorphisms and diet were: for obesity: interleukin-6 (IL-6) with daily intake; peroxisome proliferator-activated receptor gamma 2 (PPAR-gama2) and fat mass and obesity associated (FTO) with fat intake; beta-adrenergic receptor 2 (ADRB2) and melanocortin receptor 4 (MCR4) with carbohydrate intake; or reduction in body weight: uncoupling proteins (UCPs) with restriction of energy; for leptinemia: leptin receptor (LEPR) with restriction of energy; for diabetes mellitus: PPAR-gama2 with fat intake; for hypertriglyceridemia: fatty acid-binding protein 2 (FABP2) with fat intake. The data demonstrated suggest that nutritional genomics is important for the development of obesity and diabetes mellitus.