The HIV epidemic is widely recognised as having prompted one of the most remarkable intersections ever of illness, science and activism. The production, circulation, use and evaluation of empirical scientific 'evidence' played a central part in activists' engagement with AIDS science. Previous activist engagement with evidence focused on the social and biomedical responses to HIV in the global North as well as challenges around ensuring antiretroviral treatment (ART) was available in the global South. More recently, however, with the roll-out and scale-up of large public-sector ART programmes and new multi-dimensional prevention efforts, the relationships between evidence and activism have been changing. Scale-up of these large-scale treatment and prevention programmes represents an exciting new opportunity while bringing with it a host of new challenges. This paper examines what new forms of evidence and activism will be required to address the challenges of the scaling-up era of HIV treatment and prevention. It reviews some recent controversies around evidence and HIV scale-up and describes the different forms of evidence and activist strategies that will be necessary for a robust response to these new challenges.