The development of an HIV vaccine is proving to be an unprecedented challenge. The difficulty in creating this vaccine arises from the enormous genetic variation of the virus and the unusual importance of cytotoxic T lymphocytes (CTL) in controlling its spread. Whereas traditional vaccine strategies are unlikely to confer safe and effective HIV protection, novel strategies for eliciting CTL have provided substantial clinical benefits in nonhuman primate model systems. These vaccine strategies, including plasmid DNA and live recombinant vectors, are currently being evaluated in human clinical trials.