Focus groups (N = 15 groups; 8 with girls, 7 with boys) with adolescents in high schools near Cape Town, South Africa, were used to conduct a qualitative investigation of reported reasons for using and not using substances and for having and not having sex. Adolescents reported Enhancement, Negative States, Social, and Aversive Social motivations for both substance use and sexual behavior. In addition, being addicted as a reason for using drugs and rape as a context for sexual behavior were frequently reported. Motivations against behaviors included Physical/Behavioral Consequences, Ethical Objections, Social Disapproval, and Incompatible Activities and Goals reasons. Preventive interventions should address existing motivations for and against substance use and sexual behavior to acknowledge adolescents' experiences in context.