This investigation examined the risk-resistance adaptation model for children with sickle cell disease and their primary caregivers. Participants were 55 children, ranging in age from 5 to 16 years with a mean age of 9 years 2 months, diagnosed with sickle cell disease and their primary caregivers, recruited from a university medical center. Measures included adjustment (i.e. primary caregiver and child adjustment), risk factors (i.e. disease and disability, functional independence, and psychosocial stressors), resistance factors (i.e. intrapersonal health locus of control, social-ecological), and stress processing (coping). Primary caregivers' adjustment was associated with developmental coping, changeR2 = .08, and child adaptation was associated with an internal health locus of control, changeR2 = .22. An indirect effect of primary caregivers' coping on child adjustment was found through influence on primary caregivers' adjustment, changeR2 = .11. The findings support research among other chronically ill populations that suggests an association between coping and disease adjustment. The results were interpreted to support the use of theoretically driven models in predicting the adaptation of children with chronic illness and adjustment in their caregivers.