Family-based interventions with children who are affected by HIV and AIDS are not well established. The Collaborative HIV Prevention and Adolescent Mental Health Program (CHAMP) represents one of the few evidence-based interventions tested in low-income contexts in the US, Caribbean and South Africa. This paper provides a description of the theoretical and empirical bases of the development and implementation of CHAMP in two of these countries, the US and South Africa. In addition, with the advent of increasing numbers of children infected with HIV surviving into adolescence and young adulthood, a CHAMP+ family-based intervention, using the founding principles of CHAMP, has been developed to mitigate the risk influences associated with being HIV positive.