This reports on new data and challenging questions, from a 3-year cohort of adolescents living with HIV in South Africa’s Eastern Cape. 1000 adolescents were identified from patient files in 72 government clinics, and were traced to 180 communities (94% retention rate). Rates of adherence to medication are low – from 64% in the first year, down to 35% by year 3. We try to understand why by looking at social, family, clinical and economic factors – and their interplay. More importantly, we try to understand what can be done to improve adherence and wider outcomes for these young people. For good or bad, our findings are being demanded by policymakers and governments, and the interplay of policy engagement and research impacts our decisions and priorities.