To review the role of genes and lifestyle factors, particularly dietary habits and physical activity patterns, in obesity risk as well as their potential interactions.A descriptive report of a number of genes definitely ascribed or potentially implicated in excessive fat accumulation leading to obesity as assessed by different research approaches (Mendelian transmission, genetic animal models, epidemiological association/linkage studies and genome-wide scans). Also, the involvement of macronutrient intake and composition (fat/carbohydrate) as well as the role of activity-linked energy expenditure in obesity onset is reviewed.Examples of the role of the genotype as well as of the dietary macronutrient composition/intake and sedentary/low energy cost of physical activities in obesity prevalence are reported.Both genes and everyday life environmental factors such as cultural and social mediated food intake and reduced domestic and living work activities are involved in the obesity pandemia. The occurrence of gene x gene and gene x environmental factors interactions makes it more difficult to interpret the specific roles of genetics and lifestyle in obesity risk.