A reduction in dietary fat has been widely advocated for the prevention and treatment of obesity and related complications. However, the efficacy of low-fat diets has been questioned in recent years. One potential adverse effect of reduced dietary fat is a compensatory increase in the consumption of high glycaemic index (GI) carbohydrate, principally refined starchy foods and concentrated sugar. Such foods can be rapidly digested or transformed into glucose, causing a large increase in post-prandial blood glucose and insulin. Short-term feeding studies have generally found an inverse association between GI and satiety. Medium-term clinical trials have found less weight loss on high GI or high glycaemic load diets compared to low GI or low glycaemic load diets. Epidemiological analyses link GI to multiple cardiovascular disease risk factors and to the development of cardiovascular disease and type 2 diabetes. Physiologically orientated studies in humans and animal models provide support for a role of GI in disease prevention and treatment. This review examines the mechanisms underlying the potential benefits of a low GI diet, and whether such diets should be recommended in the clinical setting.