The first clinical trial of a DNA vaccine designed to protect against malaria has just commenced. This vaccine has been designed to induce protective CD8+ T cell responses against Plasmodium falciparum infected hepatocytes. Herein, we review the rationale behind the development of vaccines that induce protective CD8+ T cells, the strategy for the development of a DNA vaccine designed to protect against falciparum malaria, and the experimental data in rodent models and nonhuman primates which has provided the foundation for trials of DNA vaccines against P. falciparum malaria in humans.