The recent FDA approval of siRNA therapeutics has re-energised the RNA interference (RNAi) field. The discovery of RNAi mediated silencing in mammalian cells and parallel availability of the whole human genome sequence allowed for creation of research tools to study gene function using siRNA. However, due to challenges in siRNA delivery and pharmacokinetics, its potential as a therapeutic was not realised until the FDA approval of the siRNA therapeutics ONPATTRO® (patisiran) and GIVLAARI® (givosiran) in 2018 and 2019, respectively. Annaleen Vermeulen and Amanda Haas at Horizon Discovery discuss how the success of these therapeutics builds on almost two decades of siRNA design and encourages the field to pursue additional gene targets for therapeutic intervention.