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Sickle cell disease (SCD) is a genetic disorder characterized by complex pathophysiological mechanisms leading to vaso-occlusive crisis, chronic pain, chronic hemolytic anemia, and vascular complications, which require considerations for exercise and physical activity. This review aims to elucidate the safety, potential benefits, and recommendations regarding exercise and training in individuals with SCD. SCD patients are characterized by decreased exercise capacity and tolerance. Acute intense exercise may be accompanied by biological changes (acidosis, increased oxidative stress, and dehydration) that could increase the risk of red blood cell sickling and acute clinical complications. However, recent findings suggest that controlled exercise training is safe and well tolerated by SCD patients and could confer benefits in disease management. Regular endurance exercises of submaximal intensity or exercise interventions incorporating resistance training have been shown to improve cardiorespiratory and muscle function in SCD, which may improve quality of life. Recommendations for exercise prescription in SCD should be based on accurate clinical and functional evaluations, taking into account disease phenotype and cardiorespiratory status at rest and in response to exercise. Exercise programs should include gradual progression, incorporating adequate warm-up, cool-down, and hydration strategies. Exercise training represents promising therapeutic strategy in the management of SCD. It is now time to move through the investigation of long-term biological, physiological, and clinical effects of regular physical activity in SCD patients., (© 2024 Wiley Periodicals LLC.)