This work summarizes our knowledge of the physiological basis of fatigue and the effects of exercise and pharmacological interventions on fatigue. Fatigue may be defined as physical and/or mental weariness resulting from exertion, that is, an inability to continue exercise at the same intensity with a resultant deterioration in performance. The concept of deconditioning in patients is discussed as well as the implications for their rehabilitation and exercise. Because fatigue may result from a number of causes, including loss of muscle mass, deconditioning, nutritional deficiencies, oxygen delivery, and anemia, it should be treated comprehensively. Antifatigue therapy should be the standard of care for most chronic conditions associated with fatigue.