More than 2 million children are infected with HIV globally. Pediatric antiretroviral therapy (ART) adherence is complex, and current levels are often suboptimal. As established treatment programs in developed settings struggle with chronic therapy and nascent treatment programs in resource-limited settings expand, the importance and challenges of good adherence to ART are becoming ever more clear. Adherence behavior is influenced by many factors, which may be categorized as characteristics of the child, the caregiver(s) and family, the regimen, and society and culture. Many of these influences complicate measurement of pediatric adherence, and there is no gold standard. This article provides a conceptual framework and evidence-based look at the factors influencing ART adherence in children and aims to identify areas for intervention for this vulnerable population in need.