IPSY (Information + Psychosocial Competence = Protection) is a universal life skills program aiming at the promotion of generic intra-and interpersonal life skills, substance specific skills (for example, resistance skills), school bonding, knowledge, and the prevention of substance misuse with a focus on alcohol and tobacco in youth. This program is based on the WHO's life skills approach as well as on theories and empirical findings concerning the development of substance misuse during early adolescence. IPSY is implemented by teachers over three years of schooling (grades 5-7 in Germany). Guided by models of translational research dealing with conditions of a successful translation of etiological findings into evidence-based prevention programs, the chapter highlights the results of a more than ten-year research program focusing on the development and evaluation of the IPSY program. Findings on long-term general effects, mediators and moderators of program effectiveness, and cross-cultural transferability of the program to other European countries are summarized and discussed in light of dissemination issues.