The objective of the present study is to review the evidence on the effectiveness concerning the Saluda program, a school-based substance use prevention protocol used amongst adolescents. We provide a description of the program content and the results from nine controlled trials evaluating the program effectiveness. Participants were Spanish students aged between 12 and 16 years old. The program was created on the basis of the results from a quantitative review focused on Spanish programs, in which the most effective components were identified. Early trials compared their results with respect to a proven-effectiveness program and an unspecific health-promotion intervention, showing positive effects. Subsequent studies focused on the effects of the program according to the type of applicant, the age of participants, and attitudinal and cognitive aspects. Recent studies focused on analysing the program components effectiveness, as well as the contribution of the assigned tasks. This study summarizes strong empiric evidence concerning the program effectiveness on both risk and protective variables, at the time that further lines to improve the program effectiveness and efficiency are established.