Economic analyses of substance misuse prevention assess the intervention cost necessary to achieve a particular outcome, and thereby provide an additional dimension for evaluating prevention programming. This article reviews several types of economic analysis, considers how they can be applied to substance misuse prevention, and discusses challenges to enhancing their international relevance, particularly their usefulness for informing policy decisions. Important first steps taken to address these challenges are presented, including the disease burden concept and the development of generalized cost-effectiveness, advances that facilitate international policy discussions by providing a common framework for evaluating health care needs and program effects.