Obesity is a complex disease that results from the interaction between lifestyle (dietary patterns and sedentary habits) and genetic factors. The recognition of a genetic basis for human obesity has driven to identify putative causal genes to understand the pathways that control body mass and fat deposition in humans as well as to provide personalized treatments and prevention strategies to fight against obesity. More than 120 candidate genes have been associated with obesity-related traits. Genome-wide association study has so far identified over 20 novel loci convincingly associated with adiposity. This review is specifically focused on the study of the effects of melanocortin 4 receptor, Peroxisome proliferator-activated receptor γ and fat mass and obesity associated (FTO) gene variants and their interactions with dietary intake, physical activity or drug administration on body weight control. The advances in this field are expected to open new ways in genome-customized diets for obesity prevention and therapy following personalized approaches.