In 1988 a group of pediatricians, developmental, clinical, child and social psychologists, anthropologists and health educators began researching in Baltimore, Maryland, on an Human Immunodefiency Virus (HIV) prevention intervention, Focus on Youth (FOY). Over the next 25 years, the questions being addressed by FOY reflected those of the global HIV research experience. During the first phase, the questions being addressed by the broader research community included: Can HIV risk behaviors be purposefully impacted by behavioral interventions? If so, how do successful interventions differ from those that are not effective? Are theory-based interventions more likely to be effective than information-only-based interventions? Can theories be translated into culturally and developmentally appropriate interventions including those that are appropriate for children and adolescents? Should parents be involved – and if so, how? During its next phase, the FOY team increasingly became concerned with a disturbing reality. A large number of interventions had been developed and some had been shown to have evidence of impact. But virtually all of these interventions had been conducted in the USA or Europe. The questions facing researchers included: With the global burden of HIV disproportionately impacting low- and middle-income countries (LMIC), especially those in southern Africa, the Caribbean and parts of Asia, what is known about the effectiveness of western-based interventions in these culturally, racially and economically disparate settings? With the exciting proliferation of interventions, federal agencies in the USA and international agencies including Joint United Nations Programme on HIV/AIDS realized the importance of assessing the research portfolio and developing metrics of effectiveness. The questions during this phase included: What is an “effective” intervention? How are effective interventions implemented in a new setting? This phase merged with the next phase as researchers and public health workers realized that the dissemination to a new community of an intervention developed and found to be effective in one community requires change. The central questions during this time included: What changes or kinds of changes can be made to an intervention without undermining its effectiveness? What aspects of an intervention cannot be changed without potentially undermining its effectiveness? What constitutes a “change”? Who should be involved in this decision-making? These efforts culminated in our current phase, one focused on implementation. We must learn more about the factors that allow an intervention to survive and thrive and selectively target these critical factors. The main objective of this paper is to review our experiences and lessons learned in developing, implementing and evaluating FOY in a wide range of socio-cultural settings over the past quarter of century.