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Sickle cell disease, an early-age genetic condition, encompasses a range of blood disorders with severe complications. This disease is characterized by the synthesis of abnormal hemoglobin molecules, which tend to polymerize due to their low solubility upon deoxygenation in the peripheral capillary beds, resulting in sickle-like red blood cells. Sickled cells lose their normal functioning and hemodynamic properties, leading to chronic fatigue as well as to episodes of painful crises. Over the last two decades, a growing body of clinical evidence has pointed out that these somatic complaints can give rise to neuropsychiatric disorders, among which anxiety and depression are the most common, that worsen the health-related quality of life in patients. At first glance, this somatic influence may be unsurprising, as both anxiety and depressive signs are prevalent in almost all chronic diseases. However, in the case of a genetic condition such as sickle cell disease whose somatic disturbances are predetermined, the fact that mood disorders can increase fatigue and pain through a psychosomatic component has attracted increasing attention. In this review, we address the hypothesis of a psychosomatic component in patients with sickle cell disease by underlining the most relevant clinical studies that have highlighted the existence of a bidirectional link between physical and psychological sequelae, which are reported to be relieved not only by pharmacological cotreatments but also by the concomitant application of cognitive behavioral therapy.