Major technical advances in the field of vaccine development have culminated in an impressive array of prototype vaccines that may well provide 'proof of principle' that vaccines against all life-cycle stages may induce a degree of protection against malaria. As the mechanisms responsible for protection against this disease are not known, and vaccines for populations at greatest risk will be applied in the presence of ongoing infection and a degree of concomitant immunity, it is essential for us to learn from the 'experiments of nature' about acquired and ongoing immunity in order to determine when and how these vaccines may be applied. Successful interventions with chemoprophylaxis or vector control have provided obvious lessons and highlight the importance of recognising the lack of correlation between infection, clinical disease and mortality. Vaccines inducing sterile immunity raise concerns about rebound mortality in populations who will undoubtedly be re-challenged later in life, hence the need to review supplementary or alternative strategies for reducing disease through immune responses to toxins or molecules inducing pathology by adherence to host endothelium. Following antigen selection there are many challenges in choosing methods of antigen delivery and adjuvants, and measuring vaccine efficacy. A successful vaccine would need to be delivered through a national programme in the context of implementation of a wide range of components required for an effective control strategy.