Risk factors, such as emotional distress and peer substance involvement, are often tested as competing influences on adolescent substance use. However, the current study examined how affect (both positive and negative) and peers (both in terms of relationship quality and substance involvement) are interactive influences on adolescent substance use. A sample of 398 high school juniors and seniors completed surveys assessing each of these domains. Results of hierarchical regression analyses showed strong associations between an adolescent's and his or her best friend's substance use. Complex interactions supported the study hypothesis in that relations between affect and adolescent substance use were context dependent, with some peer contexts enhancing risk for substance use and others dampening this risk. Implications of these findings for interventions and preventions concerning adolescent substance use are discussed.