RTS,S/AS01 is the most advanced vaccine to prevent malaria. It is safe and moderately effective. A large pivotal phase III trial in over 15 000 young children in sub-Saharan Africa completed in 2014 showed that the vaccine could protect around one-third of children (aged 5-17 months) and one-fourth of infants (aged 6-12 weeks) from uncomplicated falciparum malaria. The European Medicines Agency approved licensing and programmatic roll-out of the RTSS vaccine in malaria endemic countries in sub-Saharan Africa. WHO is planning further studies in a large Malaria Vaccine Implementation Programme, in more than 400 000 young African children. With the changing malaria epidemiology in Africa resulting in older children at risk, alternative modes of employment are under evaluation, for example the use of RTS,S/AS01 in older children as part of seasonal malaria prophylaxis. Another strategy is combining mass drug administrations with mass vaccine campaigns for all age groups in regional malaria elimination campaigns. A phase II trial is ongoing to evaluate the safety and immunogenicity of the RTSS in combination with antimalarial drugs in Thailand. Such novel approaches aim to extract the maximum benefit from the well-documented, short-lasting protective efficacy of RTS,S/AS01.