Sickle cell disease (SCD) is an autosomal, recessive hemoglobinopathy characterized by hemolytic anemia, intermittent occlusion of small vessels leading to acute and chronic tissue ischemia, and organ dysfunction. Red blood cell transfusions are a therapeutic mainstay in SCD and repeated transfusions can result in iron overload. Endocrine dysfunction is the most common and earliest organ toxicity seen in subjects with chronic iron-induced cellular oxidative damage and can be seen in those without clinical evidence of iron overload. The predicted risks of iron overload and endocrine organ failure increase with both the duration of disease requiring transfusion therapy and the number of transfusions. Assessing the state of iron-overload in patients with SCD constitutes a diagnostic challenge because of the unreliability of serum ferritin levels and the risks associated with liver biopsy. In turn, MRI is the preferred noninvasive screening tool for iron overload. This article describes the endocrine and metabolic disorders reported in patients with SCD, discusses their management, and identifies gaps in current knowledge and opportunities for future research.