Naturally acquired immunity and immunity acquired after immunization with attenuated parasites indicate that a vaccine against malaria is feasible. Several obstacles have stymied malaria vaccine development, among them our poor understanding of protective immunity and technical difficulties for studying gene and protein expression in the Plasmodium falciparum parasite. Pregnancy malaria offers a model approach for vaccine development: recent findings have elucidated the basis for disease pathogenesis and protective immunity in this syndrome, and this understanding has focused the effort to identify the optimal antigens for a pregnancy malaria vaccine. In parallel, functional genomics tools are overcoming several of the obstacles for studying protein expression in the malaria parasite, vastly accelerating the pace for antigen discovery. Together, these conceptual and technological advances allow a rational approach to vaccine antigen selection, in which a finite number of antigens are selected from the entire genome by merit of the expression patterns and specific features. These candidate antigens are then subjected to detailed studies according to criteria established by the understanding of pathogenesis and protective immunity, to identify the optimal antigens for inclusion in subunit vaccines.