Vaccines are one of the most efficient health care interventions but the generation of effective vaccines against many diseases caused by complex pathogens has proven difficult. A significant advance of the past decade has been the elucidation of the genome, proteome and transcriptome of many pathogens. This information provides the foundation for new 21st Century approaches to identify target antigens for the development of vaccines, drugs, and diagnostics. Development of an effective vaccine also requires an understanding of the type of immune response that needs to be induced by vaccination. Thus other work in the laboratory focuses on the molecular profiling of adaptive immunity to Plasmodium infection in humans using systems immunology; and dissecting the mechanisms of immunity in murine models. This talk will discuss progress using systems-based approaches to advance the rational development of a vaccine against malaria, and inform the development of vaccines against other diseases caused by complex pathogens.