Physiological and behavioural systems are tolerant of excess energy intake and responsive to energy deficits. Weight loss (WL) changes body structure, physiological function and energy balance (EB) behaviours, which resist further WL and promote subsequent weight regain. Measuring and understanding the response of EB systems to energy deficits is important for developing evidence-based behaviour change interventions for longer-term weight management. Currently, behaviour change approaches for longer-term WL show modest effect sizes. Self-regulation of EB behaviours (e.g. goal setting, action plans, self-monitoring, relapse prevention plans) and aspects of motivation are important for WL maintenance. Stress management, emotion regulation and food hedonics may also be important for relapse prevention, but the evidence is less concrete. Although much is known about the effects of WL on physiological and psychological function, little is known about the way these dynamic changes affect human EB behaviours. Key areas of future importance include (i) improved methods for detailed tracking of energy expenditure, balance and by subtraction intake, using digital technologies, (ii) how WL impacts body structure, function and subsequent EB behaviours, (iii) how behaviour change approaches can overcome physiological resistance to WL and (iv) who is likely to maintain WL or relapse. Modelling physiological and psychological moderators and mediators of EB-related behaviours is central to understanding and improving longer-term weight and health outcomes in the general population.