This article explores how advances in synthetic biology, and the potential threat of deliberately recreating and spreading smallpox, are affecting the multilateral debate on the remaining variola virus stocks. It draws on in-depth, semi-structured interviews with 10 high-profile, European-based experts in biosecurity and synthetic biology. Four overarching themes affecting the retention or destruction debate are discussed, relating to biosecurity, dangerous knowledge, accidental releases, and eradication. We conclude that while synthetic biology seems to affect all the main discourses in the variola stocks debate, a range of views is present and it is not apparent that advances in synthetic biology are causing a shift toward either retention or destruction of the stocks.