RTS,S is the world's most advanced malaria vaccine candidate and is intended to protect infants and young children living in malaria endemic areas of sub-Saharan Africa against clinical disease caused by Plasmodium falciparum. Recently, a pivotal Phase III efficacy trial of RTS,S began in Africa. The goal of the programme has been to develop a vaccine that will be safe and effective when administered via the Expanded Program for Immunization (EPI) and significantly reduce the risk of clinically important malaria disease during the first years of life. If a similar reduction in the risk of severe malaria and other important co-morbidities associated with malaria infection can be achieved, then the vaccine could become a major new tool for reducing the burden of malaria in sub-Saharan Africa. Encouraging data from the ongoing phase II programme suggest that these goals may indeed be achievable. This review discusses some of the unique challenges that were faced during the development of this vaccine, highlights the complexity of developing new vaccine technologies and illustrates the power of partnerships in the ongoing fight against this killer disease.