Evidence-based practice has become a methodology to support decisions and actions in public health, including those aimed at preventing drug use. In this sense, the evolution of the explanatory models of the phenomenon of addictions has been guided by advances in scientific research, making it possible to generate, test, modify, enrich and improve the preventive programs that have emerged in Mexico over the years and that, in some cases, continue to operate. The lessons learned and the knowledge accumulated in the various approaches to addiction care have been fundamental: the legal-ethical model, with its moral and behavioral roots; the medical-health model, of a scientific nature and health-oriented; the sociocultural model, of greater complexity, which takes into account a macrosocial perspective related to socio-community dynamics; the psychosocial model, which conceives addictions as behavioral disorders to resolve conflicts of the people in their microsocial environment and includes drug use in the field of mental health; and the more modern integrative model, with a holistic approach is essential for successful prevention and sustainable long-term treatment. From successful experiences and from facing common challenges in the national context, it has been possible to better understand the characteristics that modulate the initiation and maintenance of substance use of one person with respect to another. It has also helped to identify key points for developing strategies to address specific risk factors, as well as to define methods that promote protective factors. In this way, by taking into account quality standards, theoretical principles and methodological guidelines that guarantee rigor and best practices, progress has been made in the design of preventive programs based on the characteristics and needs of the Mexican population. The dynamic nature of the addiction phenomenon poses new challenges, but the evolution of knowledge and integration of new technologies also offers the opportunity for a healthier future for all.