Unless something dramatic happens, the AIDS epidemic will be under control across the world by 2022. The number of new infections will continue to fall; there will be virtually no vertical transmission from mothers to infants; and for those infected, treatment will be increasingly effective and simple, with fewer side effects. But AIDS will not end by 2030, as hoped by the UNAIDS 2015 report. ‘Big issues and major challenges’ examines key areas for the challenge ahead: the need to focus on specific areas and populations, harnessing new technologies, and the sensible use of finance. In 2016 there is ample reason to be optimistic, but there must be continued vigilance.