Purpose of reviewDespite much current debate regarding central and peripheral neural mechanisms which may be responsible for the onset of fatigue during prolonged exercise, maintenance of nutritional and hydration status remains critical for successful participation in ultra‐endurance exercise. This review focuses on substrate and fluid homeostasis during ultra‐endurance exercise and the use of nutritional supplementation both as ergogenic aid and to attenuate exercise‐induced immunosuppression.Recent findingsCurrent evidence continues to support mandatory high carbohydrate intakes (1) before the event to maximize muscle glycogen stores, (2) during the event to prevent hypoglycaemia and (3) after the event to optimize post‐event repletion of endogenous carbohydrate stores. No consistent performance benefit has yet been shown following a high‐fat diet. Greater utilization of intrafascicular triglyceride stores appears to account for additional fat utilization in females. Recent trends towards excessive fluid intake have resulted in frequent reports of hyponatraemic hyperhydration in ultra‐distance athletes, with greater incidence in women than in men. Carbohydrate supplementation during the event attenuates immunosuppressive hormonal and cytokine responses to ultraendurance exercise, but may impair vitamin C absorption, while the ergogenic value of caffeine supplementation in ultra‐endurance performance is currently being questioned.SummaryMeeting macronutrient and fluid intake demands remains an important priority for ultra‐endurance athletes. Yet these athletes are reported to present with a high incidence of disordered eating patterns during periods of training, and excessive fluid replacement strategies have resulted in an increased incidence of water intoxication with resultant central nervous system dysfunction.