Nucleic acid vaccines provide an exciting new alternative approach to developing the multiantigen vaccines designed to induce protective antibody and T-cell responses against Plasmodium proteins that many experts believe will be required for effective protection against malaria. As a first step in this process, we produced a plasmid DNA vaccine that includes the gene encoding the P. yoelii circumsporozoite protein (PyCSP). This vaccine induced higher levels of antibodies and cytotoxic T lymphocytes against PyCSP than immunization with irradiated sporozoites, and protected 9 of the first 16 mice immunized. Work is now in progress to optimize immunization regimens, establish the mechanisms of protective immunity induced by the vaccine, and to determine whether protective immunity can be increased by vaccinating with multiple nucleic acid vaccines designed to produce immune responses against multiple targets.