Objective: A theoretical model was used to examine the impact of risk and resistance factors on the psychological adjustment of children and adolescents with sickle cell disease (SCD). Participants: One hundred eighteen children and adolescents with SCD receiving treatment at a comprehensive sickle cell center and their mothers. Measures: Included risk factors (condition parameters, functional independence, and disability stressors), resistance factors (stress processing, intrapersonal factors, and social ecological factors), and adjustment. Results: Adaptive behavior was associated with child maladjustment, severity of disability was associated with disability stress, and child competence was associated with child maladjustment. Coping did not moderate the association between stress and maladjustment, and adaptive behavior and stress did not mediate the association between severity of disability and maladjustment, as the model had predicted. Conclusions: Results support the continued use of theoretically driven models to investigate the adjustment of children and adolescents with chronic conditions and to promote comparisons of different chronic illnesses and disabling conditions. The findings indicate possible avenues for clinical intervention with children and adolescents with SCD.