The present study examined qualitative differences in relationships between substance use and adjustment at five points of measurement from late childhood to young adulthood. The sample consisted of 133 participants from the New York Longitudinal Study. Cluster analysis was used to partition the sample into groups on the basis of multiple substance use (tobacco, alcohol, marijuana, and other substances) at each point of measurement. Cluster membership was most strongly related to adjustment differences in late childhood and young adulthood. Results from a series of ANOVAs indicated that individuals consistently using the highest amounts of multiple substances exhibited the lowest levels of psychological adjustment.