Many African Americans with sickle cell disease (SCD) also experience significant economic hardship. Yet, few studies of the psychosocial effects of SCD employ designs robust enough to control socioeconomic factors. This study compares the functioning of families with SCD to that of healthy controls matched for race and socioeconomic status. In general, functioning within SCD and control families did not differ. However, parents granted less autonomy to, and were less involved in the schooling of, children with SCD. Overall, SCD had a greater impact on children’s social and academic competence than on their emotional functioning. However, adolescents with SCD and their siblings were at greater risk for mental health difficulties than were controls. The more SCD interfered with living normally, the greater the risk of psychological dysfunction. Importantly, emotional well-being in parents moderated the adverse effects of SCD on children. Similarly, racial consciousness, religiosity, and emotional support enhanced parental coping.