In the United States, sickle cell disease primarily affects people of African descent, and the multisystemic complications caused by the resultant vaso-occlusive state create a multitude of diagnostic considerations. In the musculoskeletal system, likelihood is high for avascular necrosis of the femoral humeral head, as a consequence of skeletal infarcts, and also for leg ulceration and osteomyelitis; in the eyes, the incidence of proliferative retinopathy is high; in the urinary tract, dehydration is common, and causes for renal failure are many; in the pulmonary system, pneumonia is of prime concern, as are sickle cell chest syndrome (from occlusion within the microvasculature of the lung) and the deadly sickle cell chronic lung disease, for which pulmonary function tests are important in early asymptomatic stages. Cholelithiasis occurs in 40% of young adult patients with sickle cell disease and can be confused with sickle cell hepatopathy, and rheumatologic and immunologic diseases can occur concomitantly with sickle cell disease, with similar symptoms. The chance for stroke in patients with sickle cell disease is 25%, and early recurrence is common, although the pathogenesis has been more clearly elucidated through computed tomography and magnetic resonance imaging. Infection with Streptococcus pneumoniae has high mortality because of the asplenia associated with sickle cell disease.