Global levels of overweight and obesity continue to rise and successful interventions to combat this epidemic are limited in number and suitability. When energy intake exceeds that expended, the excess energy accumulates as body fat. Although energy balance is regulated by hypothalamic mechanisms, these can be overridden by the activation of hedonic brain systems. This apparent hierarchy is exacerbated by the widespread availability of inexpensive, palatable and energy-dense food in the current obesogenic environment, giving rise to energy overconsumption and thereby contributing to the increase in overweight and obesity. The European Commission recognised a need for further research to enhance understanding of the relatively poorly understood mechanisms underpinning hunger and satiety, with a view to providing an evidence base from which novel strategies could be developed to tackle the escalating crisis. Full4Health (Understanding food-gut-brain mechanisms across the lifespan in the regulation of hunger and satiety for health) is a project funded under Framework Programme 7 (FP7), conceived to fulfil this aim. This article describes selected recent research from Full4Health and discusses how new mechanistic findings related to physiological responses to food might be adapted and harnessed to provide alternative ways to address the global problems related to positive energy balance.