I provide a systematic review of trials of school-based smoking prevention programs that had at least 15 sessions, preferably with some in high school, that reported significant short-term effects, and that included long-term follow-up. This is supplemented with a description of some other programs that produce short-term effects that portend large long-term effects. I conclude that school-based programs can have long-term effects of practical importance it they: include 15 or more sessions over multiple years, including some in high school; use the social influence model and interactive delivery methods; include components on norms, commitment not to use, intentions not to use, and training and practice in the use of refusal and other life skills; and use peer leaders in some role. School-based programs of this type can reduce smoking onset by 25–30%, and school plus community programs can reduce smoking onset by 35–40% by the end of high school. Some early childhood programs that do not have smoking prevention as their main aim, including home nursing, the Good Behavior Game, the Positive Action program and others, seem to change the developmental trajectories of children so that they are less likely to engage in multiple problem behaviors, including smoking, as adolescents. This review makes it clear that effective school-based smoking prevention programs exist and can be adopted, adapted and deployed with success – and should be.