Hypogonadism is common in men with sickle cell disease (SCD). This condition is associated with impaired physical and sexual maturation, infertility, priapism, bone loss, and cognitive decline. Additionally, some treatments for SCD exacerbate hypogonadism. The pathophysiology of hypogonadism in SCD is undefined. Primary hypogonadism is considered to be the predominant form. Basic science studies have suggested increased NOX-derived oxidative stress in the testis and reduced transport of cholesterol to the inner mitochondrial membrane of Leydig cells as the principal mechanisms for this hormonal abnormality. Secondary hypogonadism and compensated hypogonadism have also been observed. It is also not known whether some other health-related issues are consequences of low testosterone levels or are related to the disease itself. Exogenously administered testosterone improves some of the adverse health-related consequences of SCD, but it decreases intratesticular testosterone production with potentially adverse events on fertility. Targeting mechanism-specific molecular pathways of testosterone production in the SCD testis by pharmacologic activation of translocator protein, involved in cholesterol transport in Leydig cells, is proposed as a potential treatment to correct primary hypogonadism without affecting intratesticular testosterone production.