The increase in the incidence of HIV/AIDS among minorities in the United States and in certain developing nations has prompted new intervention priorities, stressing the adaptation of efficacious interventions for diverse and marginalized groups. The experiences of Florida International University's AIDS Prevention Program in translating HIV primary and secondary prevention interventions among these multicultural populations provide insight into the process of cultural adaptations and address the new scientific emphasis on ecological validity. An iterative process involving forward and backward translation, a cultural linguistic committee, focus group discussions, documentation of project procedures, and consultations with other researchers in the field was used to modify interventions. This article presents strategies used to ensure fidelity in implementing the efficacious core components of evidence-based interventions for reducing HIV transmission and drug use behaviors and the challenges posed by making cultural adaptation for participants with low literacy. This experience demonstrates the importance of integrating culturally relevant material in the translation process with intense focus on language and nuance. The process must ensure that the level of intervention is appropriate for the educational level of participants. Furthermore, the rights of participants must be protected during consenting procedures by instituting policies that recognize the socioeconomic, educational, and systemic pressures to participate in research.