Almost four decades since AIDS was first reported in Africa, the epidemic has reached a watershed moment where progress in prevention, care and support programs confronts intransigent socioeconomic and gender rights barriers and emerging funding uncertainties. While there are grounds for cautious optimism that the incidence of HIV infections and AIDS-related mortality can be further reduced, they cannot, by themselves, end the epidemic. This will require overcoming gendered inequalities, HIV stigma and neglect of high-risk youth and socially peripheralized groups.