Obesity is a major global health problem and predisposes individuals to several comorbidities that can affect life expectancy. Interventions based on lifestyle modification (for example, improved diet and exercise) are integral components in the management of obesity. However, although weight loss can be achieved through dietary restriction and/or increased physical activity, over the long term many individuals regain weight. The aim of this article is to review the research into the processes and mechanisms that underpin weight regain after weight loss and comment on future strategies to address them. Maintenance of body weight is regulated by the interaction of a number of processes, encompassing homoeostatic, environmental and behavioural factors. In homoeostatic regulation, the hypothalamus has a central role in integrating signals regarding food intake, energy balance and body weight, while an 'obesogenic' environment and behavioural patterns exert effects on the amount and type of food intake and physical activity. The roles of other environmental factors are also now being considered, including sleep debt and iatrogenic effects of medications, many of which warrant further investigation. Unfortunately, physiological adaptations to weight loss favour weight regain. These changes include perturbations in the levels of circulating appetite-related hormones and energy homoeostasis, in addition to alterations in nutrient metabolism and subjective appetite. To maintain weight loss, individuals must adhere to behaviours that counteract physiological adaptations and other factors favouring weight regain. It is difficult to overcome physiology with behaviour. Weight loss medications and surgery change the physiology of body weight regulation and are the best chance for long-term success. An increased understanding of the physiology of weight loss and regain will underpin the development of future strategies to support overweight and obese individuals in their efforts to achieve and maintain weight loss.