Among side effects, fatigue is the most common symptoms described by patients in a wide range of chronic diseases. Described as “being drained physically, but also mentally and emotionally,” often seen as the most distressing symptom, fatigue interferes with daily life by impairing quality of life, functional capacity, self-perception and social participation; it is potentially debilitating and it is associated with significant morbidity. Yet it remains relatively unknown, me-considered mis-assessed and mis-treated, partly due to the still limited understanding of its pathophysiology, its complex assessment, the lack of effective treatments (no medicine against fatigue apart specific pathological conditions) and of training to its management. The optimal management of fatigue is a key issue in the course of care, helping to reduce the burden associated with the disease and treatments. We will review the scientific evidence showing that PA is one of the best ways to handle the fatigue and fight against PA rupture, which is generally following the diagnosis, without compromising ongoing treatments. However, fatigue is a major obstacle to adherence to a regular PA. Systematic rest is an aggravating factor of fatigue. This is why only well-designed and conducted PA programs will help a person to start intelligently activity again (i.e., programs involving evaluation, programming, individualization in their design, and adapted support and monitoring in their implementation, all framed by a qualified professional). We will develop latest recommendations for the management of fatigue by PA and innovative indications for optimal programs.