An intronic single nucleotide polymorphism (SNP) (rs9939609) close to the fat mass and obesity associated gene (FTO) was the first SNP to be discovered with common variants linked to body mass index; at least seven studies in humans have implicated this SNP with variations in food intake and satiety, and four studies have rejected an effect on energy expenditure normalized for body weight. Fischer et al. recently constructed a mouse in which the homologous Fto gene was inactivated (Fto(-/-)) and showed that these mice were protected from obesity. This observation strongly implicates the effects of the intronic SNP rs9939609 as arising due to an effect on the closest gene (FTO). However, the suggested mechanism underlying this effect in mice was opposite to that in humans. The Fto(-/-) mice showed no significant differences in food intake relative to wild-types litter-mates but had an elevated metabolic rate. The apparent contrasting effects of the gene in humans and mice is worthy of closer investigation.