This study examined the relationship between the domains of environmental factors, family illegal drug use, parental child-rearing practices, maternal and adolescent personality attributes, and adolescent illegal drug use. A nonclinical sample of 2,837 Colombian youths and their mothers were interviewed about intrapersonal, interpersonal, and environmental factors in their lives. Results indicated that certain environmental factors (e.g., violence, drug availability, and machismo), family drug use, a distant parent-child relationship, and unconventional behavior are risk factors for adolescent illegal drug use. As hypothesized, results showed that the adverse effects of family illegal drug use on adolescent drug use can be buffered by protective parental child-rearing practices and environmental factors, leading to less adolescent illegal drug use. Prevention and treatment efforts should incorporate protective environmental, familial, and intrapersonal components in order to reduce adolescent illegal drug use.