This study tested two competing models of differential susceptibility and diathesis-stress in a prospective longitudinal study of African American youths (N = 935). It examined whether individual variations in the functioning of the hypothalamic-pituitary-adrenocortical axis at age 11 interact with middle childhood parent-child relationship quality to predict mental and physical health problems in adolescence (ages 11-15 years old). Adolescent boys with lower levels of cortisol reactivity to laboratory challenges had the highest levels of internalizing problems if they experienced a high conflictual relationship with their parents. Equally low-reactive boys, however, reported the lowest number of physical illnesses if their relationship with their parents was characterized by high levels of intimacy and support.