Sickle cell disease (SCD), the most common genetic disease screened for in the newborn period, occurs in ∼1 in 2400 newborns in the general population and 1 in 400 individuals of African descent in the United States. Despite the relative high prevalence and low pediatric mortality rate of SCD when compared with other genetic diseases or chronic diseases in pediatrics, few evidence-based guidelines have been developed to facilitate the transition from pediatrics to an internal medicine or family practice environment. As with any pediatric transition program, common educational, social, and health systems themes exist to prepare for the next phase of health care; however, unique features characterizing the experience of adolescents with SCD must also be addressed. These challenges include, but are not limited to, a higher proportion of SCD adolescents receiving public health insurance when compared with any other pediatric genetic or chronic diseases; the high proportion of overt strokes or silent cerebral infarcts (∼30%) affecting cognition; risk of low high school graduation; and a high rate of comorbid disease, including asthma. Young adults with SCD are living longer; consequently, the importance of transitioning from a pediatric primary care provider to adult primary care physician has become a critical step in the health care management plan. We identify how the primary care physicians in tandem with the pediatric specialist can enhance transition interventions for children and adolescents with SCD.