Without strengthened health systems, significant access to antiretroviral (ARV) therapy in many developing countries is unlikely to be achieved. This paper reflects on systemic challenges to scaling up ARV access in countries with both massive epidemics and weak health systems. It draws on the authors' experience in southern Africa and the World Health Organization's framework on health system performance. Whilst acknowledging the still significant gap in financing, the paper focuses on the challenges of reorienting service delivery towards chronic disease care and the human resource crisis in health systems. Inadequate supply, poor distribution, low remuneration and accelerated migration of skilled health workers are increasingly regarded as key systems constraints to scaling up of HIV treatment. Problems, however, go beyond the issue of numbers to include productivity and cultures of service delivery. As more countries receive funds for antiretroviral access programmes, strong national stewardship of these programmes becomes increasingly necessary. The paper proposes a set of short- and long-term stewardship tasks, which include resisting the verticalisation of HIV treatment, the evaluation of community health workers and their potential role in HIV treatment access, international action on the brain drain, and greater investment in national human resource functions of planning, production, remuneration and management.