Obesity is now classified as an epidemic by the World Health Organisation and represents one of the greatest threats to the health of the developed world. It is estimated that there are over one billion overweight adults worldwide and an estimated 22 million children under 5 are obese, with annual figures rising sharply. Obesity increases the risk of heart disease, type 2 diabetes, stroke, some forms of cancer, arthritis, respiratory disease and translates into healthcare costs of over half a billion pounds every year in the UK alone. The obesity crisis in the developed world is largely attributed to the easy availability of cheap, calorie dense, palatable food accompanied by an increasingly sedentary lifestyle. The current crisis has prompted public health initiatives to improve diet and promote exercise, however these have proved largely ineffective, highlighting the urgent need for improved therapies for the treatment of obesity. Weight regulation in individuals depends on energy intake (in the form of food) and energy expenditure. Hunger leads to initiation of eating and when a meal is ingested, satiety hormones contribute to digestion and a feeling of fullness. Central circuits in the brain integrate satiety signals and signals of long term energy status to produce a coordinated response to the change in nutritional status. The nuclei of the hypothalamus and brainstem are important regions for regulation of energy homeostasis. The actuate nucleus (ARC) can access signals from the periphery. The signals act on two distinct neuronal populations. One population co-expresses the orexigenic Agouti-related Peptide (AgRP) and Neuropeptide Y (NPY); the other population releases cocaine and amphetamine regulated transcript (CART) and proopiomelanocortin (POMC), which inhibit feeding. Both of these populations project to the paraventricular nucleus (PVN) and other nuclei involved in energy regulation. Gut hormones are released in response to a meal acting on both central neural circuits and peripheral tissues. They affect diverse physiological functions including appetite, gastrointestinal motility and acid secretion, nutrient absorption and cell proliferation. Receptors for gut hormones can be found on neuronal populations within the actuate nucleus of the hypothalamus. Recent work has identified the gut hormones PYY, oxyntomodulin and pancreatic polypeptide (PP) that inhibit appetite, and ghrelin, which stimulates appetite. These hormones occur naturally, are active within the plasma range observed in humans and may therefore represent a novel approach to the treatment of obesity. Our continuing research has identified oxyntomodulin and PYY as strong candidates for therapeutic agents.