The prevalence of childhood obesity is increasing in many countries and confers risks for early type 2 diabetes, cardiovascular disease and metabolic syndrome. In the presence of potent 'obesogenic' environments not all children become obese, indicating the presence of susceptibility and resistance. Taking an energy balance approach, susceptibility could be mediated through a failure of appetite regulation leading to increased energy intake or via diminished energy expenditure. Evidence shows that heritability estimates for BMI and body fat are paralleled by similar coefficients for energy intake and preferences for dietary fat. Twin studies implicate weak satiety and enhanced food responsiveness as factors determining an increase in BMI. Single gene mutations, for example in the leptin receptor gene, that lead to extreme obesity appear to operate through appetite regulating mechanisms and the phenotypic response involves overconsumption and a failure to inhibit eating. Investigations of robustly characterized common gene variants of fat mass and obesity associated (FTO), peroxisome proliferator-activated receptor (PPARG) and melanocortin 4 receptor (MC4R) which contribute to variance in BMI also influence the variance in appetite factors such as measured energy intake, satiety responsiveness and the intake of palatable energy-dense food. A review of the evidence suggests that susceptibility to childhood obesity involving specific allelic variants of certain genes is mediated primarily through food consumption (appetite regulation) rather than through a decrease in activity-related energy expenditure. This conclusion has implications for early detection of susceptibility, and for prevention and management of childhood obesity.