This document offers practical guidance for programs aimed at addressing the needs of children made vulnerable by HIV/AIDS. It provides key definitions, guiding principles, and important considerations for programming decisions. The guidance clarifies PEPFAR/Emergency Plan priorities and the activities that it will fund related to orphans and vulnerable children (OVC). It builds on the principles outlined in the U.S. Five-Year Global HIV/AIDS Strategy, and extends the vision and guidance of the President’s Emergency Plan. The knowledge and evidence base underpinning this guidance continues to grow. With new experiences and learning over time, this OVC Guidance is expected to evolve. Updates will incorporate new insights, improved practices and lessons learned.