As global commitment grows to protect and support children affected by HIV and AIDS, questions remain about how best to meet the needs of these children in low prevalence settings and whether information from high prevalence countries can appropriately guide programming in these settings. A 2007 search for the evidence in low prevalence settings on situational challenges of HIV and AIDS-affected children and interventions to address these challenges identified 413 documents. They were reviewed and judged for quality of documentation and scientific rigor. Information was compiled across eight types of challenges (health and health care, nutrition and food security, education, protection, placement, psychosocial development, socioeconomic status, and stigma/ discrimination); and also assessed was strength of evidence for situational and intervention findings. Results were compared to three programming principles drawn from research in high prevalence countries: family-centered preventive efforts, treatment, and care; family-focused support to ensure capacity to care for and protect these children; and sustaining economic livelihood of HIV and AIDS-affected households. Findings show that children affected by HIV and AIDS in low prevalence settings face increased vulnerabilities similar to those in high prevalence settings. These findings support seeking and testing programmatic directions for interventions identified in high prevalence settings. However, low prevalence settings/countries are extremely diverse, and the strength of the evidence base among them was mixed (strong, moderate, and weak in study design and documentation), geographically limited, and had insufficient evidence on interventions to draw conclusions about how best to reduce additional vulnerabilities of affected children. Information on family, economic, sociocultural, and political factors within local contexts will be vital in the development of appropriate strategies to mitigate vulnerabilities.