An editorial notes that the most advanced candidate vaccine against dengue viruses (CYD-TDV), is progressing toward potential registration and review by the WHO in 2016. The current updated efficacy results are from the third year of hospital-based surveillance from two phase 3 trials (CYD14 and CYD15) and the third and fourth years of one phase 2b trial (CYD23/57). The commentator discusses the possible reasons for the finding that CYD-TDV vaccination was associated with an elevated risk of hospitalization for dengue among children younger than 9 years of age (but most markedly, among those 2 to 5 years of age) when they were naturally infected in the third year after vaccination. He concludes overall that the CYD-TDV trials have been superbly conducted and are hugely informative; they have delivered major insights into disease burden, clinical epidemiology, and immunity, and also highlighted knowledge gaps.