Controversy regarding the aetiology and treatment of patients with chronic fatigue syndrome (CFS) continues to affect the medical professions. The Cochrane collaboration advises practitioners to implement graded exercise therapy for CFS sufferers using cognitive behavioural principles. In contrast there is evidence that exercise can induce symptom exacerbations in CFS where too vigorous exercise/activity promotes immune dysfunction, which in turn increases symptoms in patients with CFS. When designing and implementing an exercise programme it is important to be aware of both these seemingly opposing view points in order to deliver a programme without any detrimental effects on CFS pathophysiology. Using evidence from both the biological and clinical sciences, the present manuscript explains that graded exercise therapy for people with CFS can be safely undertaken without detrimental effects to the immune system. Exercise programs should be designed to cater for individual physical capabilities and should also account for the fluctuating nature of symptoms commonly reported by people with CFS. In line with cognitive behaviourally and graded exercise-based strategies, self-management for people with CFS involves encouraging the patients to pace their activities and respect their physical and mental limitations with the ultimate aim of improving their everyday function