This study investigated the relationships among sleep problems, learning difficulties and substance use in adolescence. Previous research suggests that these variables share an association with executive functioning deficits, and are intertwined. The sample comprised 427 adolescents (M age = 16 years) attending remedial schools and 276 adolescents (M age = 15 years) attending a mainstream school in Cape Town, South Africa. Participants completed anonymous self-report questionnaires. Results indicated that adolescents without learning difficulties were more likely to use tobacco, methamphetamine and cannabis, whereas those with learning difficulties engaged in more inhalant use. Adolescents who had more sleep problems were more likely to use tobacco, alcohol, methamphetamine, cannabis, inhalants, cocaine, ecstasy and any other illegal drug. Adolescents with learning difficulties had more sleep problems than those without learning difficulties. However, sleep problems remained independently associated with tobacco, cannabis and inhalant use when learning difficulties were taken into account. (Contains 5 tables.)