Sickle cell anemia (SCA or SS homozygous sickle cell disease) is an inherited blood disorder caused by single nucleotide substitution in the β-globin gene that renders their hemoglobin (HbS) much less soluble than normal hemoglobin (HbA) when deoxygenated. The polymerization of HbS upon deoxygenation is the basic pathophysiologic event leading to RBC sickling, hemolysis, vasoocclusion and ultimately to chronic organ damage. The metabolic changes imposed by exercise may initiate sickling and vaso-occlusive episodes. Further, in patients with SCA, exercise limitation may be related to anemia or chronic complications such as pulmonary vascular disease, congestive heart failure and chronic parenchymal lung disease. Few studies have investigated the cardiorespiratory responses of patients with SCA during either symptom-limited maximal exercise test on cyclo-ergometer or during a six minute walk test. Therefore, patients are advised to start exercise slowly and progressively, to maintain adequate hydration during and after exercise, to avoid cold exposure or sudden change in temperature, and to avoid sports associated with mechanical trauma. There are, however, lack of evidence to allow practitioners to prescribe an exercise program for patients with SCA, and individuals are usually encouraged to exercise on a symptom-limited basis. Finally, this review will also highlight the basic principles that are often used for exercise practice and could be used for exercise prescription and rehabilitation in patients with sickle cell anemia.