Research concerning the etiology and prevention of substance misuse has led to the development of preventive interventions that are theory-based and effective. One such approach, Life Skills Training (LST), targets key etiologic factors using a conceptual framework derived from social learning theory and problem behavior theory. LST has been extensively tested in a series of randomized trials and found effective in preventing the use/misuse of alcohol, tobacco, marijuana, and other psychoactive drugs. Research demonstrates that it is effective when implemented under different delivery conditions, by different program providers, with different age groups, and with different populations. Follow-up studies provide evidence of the long-term effectiveness of LST. Independent economic analysis indicates that LST produces cost savings of as much as $38 for every dollar invested. Finally, LST offers the potential of reducing other health risk behaviors and fostering academic success.