It is becoming increasingly recognised that early‐life nutritional, metabolic and environmental factors can have a long term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to its adult life‐style and nutritional environment depends not only on their genetic susceptibility but also their previous early‐life experiences. The current research challenge is to determine the primary pathways contributing to “non‐ or epi‐genetic” causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life‐course modelling and diet‐induced fetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early‐life determination of body weight, body composition and energy balance. We will summarise current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of fetal nutrition. Ultimately we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues. This article is protected by copyright. All rights reserved.