Vaccines are one of the most efficient health care interventions but vaccines against many diseases caused by complex pathogens are not available. 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. Using malaria as a model, we are pursuing a rational approach to vaccine design for infectious diseases caused by complex pathogens. We are using technology platforms such as protein microarrays, high throughput protein production, and epitope prediction algorithms with specimens from individuals naturally or experimentally exposed to the causative pathogen to identify and prioritize those antigens and epitopes most likely to be effective as vaccine targets. We have established that T cell and antibody responses to the Plasmodium parasite are broadly distributed throughout the proteome and many newly identified antigens are more immunogenic than antigens identified historically. Furthermore, antigens that are highly reactive for T cells are not serodominant for antibody responses, suggesting that different approaches are required to identify the most effective targets of T cell responses and antibody responses. Our studies have established proof-of-concept for both T cell and antibody based approaches to identify antigens and epitopes which represent promising candidates for next generation malaria vaccine development. These approaches may overcome the problem of poorly immunogenic, poorly protective vaccines that has plagued vaccine developers for many years.