South Africa's health care system is struggling to respond to the devastating impact of HIV/AIDS while at the same time respecting its postapartheid mandate to provide equitable health services to all. These unprecedented challenges are forcing a rethinking and reorganization of health resources and systems and a reappraisal of the role of nurses in the care of complex and chronic illness. Increasingly, the scale-up of HIV services is being reconceptualized to match both the urgent need for prevention, care, and treatment and the national vision of decentralized primary health care. HIV scale-up has triggered innovations in nurse training, task shifting, retention, and scope of practice that need not remain HIV specific. Lessons learned in the context of HIV have the potential to enhance nursing practice and human resources for health more generally, strengthening South Africa's health systems and improving access to effective health services.