Although a necessary component of good program management and accountability, monitoring data do not usually provide answers to questions about whether, how, and why a specific program works. More in-depth, systematic inquiry is needed to do this. In this article, the authors focus on the evaluation of human immunodeficiency virus (HIV)-prevention interventions. HIV prevention was selected as the area of choice because it is under pressure to prove its effects within a context of competing demands for acquired immunodeficiency syndrome (AIDS) treatment that are beginning to scale up around the world. Hence, HIV-prevention evaluation is a pertinent and timely matter. Because of the urgency to tackle the HIV/AIDS problem, many prevention programs have rushed to carry out interventions without sufficient grounding in baseline research, models of causality, or lessons learned from small-scale pilot projects. In the haste to mobilize a rapid response, resources for HIV prevention have often been allocated suboptimally, supporting the scaling up of interventions without solid evidence of their effectiveness. This has compromised the ability to control new infections. Further rises in HIV incidence will be slowed only by massive expansion of prevention efforts. HIV-prevention interventions have maximum potential for impact when they are part of a comprehensive package of interventions and are spearheaded by governments that break the silence around HIV/AIDS and deploy sufficient human and financial resources. The effects of these interventions can be enhanced when there are wider public health and development strategies present. Because the epidemic is constantly shifting, HIV-prevention efforts must continue to be tailored to developments in the epidemic and linked to evaluations that confirm their success or failure. The charge for researchers and program evaluators, then, is to estimate which approaches work best for specific target populations in different epidemiological settings with a given level of inputs in order to allocate resources in a cost-effective manner and for public health practitioners to implement evidence-based interventions. (Contains 2 tables and 1 figure.)