The global spread of human immunodeficiency virus (HIV) and the human suffering left in its wake have made AIDS a global heath priority. Yet the capacity of HIV to mutate and evolve rapidly has made combating this virus a tremendous challenge. While the obstacles to creating an effective HIV vaccine are formidable, advances have been made on many fronts with the development of novel vectors (62), adjuvants, and antigen design strategies. Live attenuated vaccines have been shown to confer some protection against heterologous challenge viruses in the simian immunodeficiency virus (SIV)/macaque model, providing opportunities to explore the biologic underpinnings of vaccine protection. Equally important is our growing understanding of the biology of acute infection (35, 48, 82, 84) and the role of immune responses in containing viral replication in long-term nonprogressor patients. This review focuses on summarizing strategies for contending with HIV variation in designing a T-cell-based component of a vaccine. We will summarize recent progress by many groups in a number of complementing areas, assessing the impact of diversity in a primate model system, polyepitope vaccines, conserved-region vaccines, central protein design, polyvalent natural proteins, and polyvalent central proteins. The strategies that prove most effective for priming innate cells and T and B cells ultimately could be combined with the best strategies to deal with the magnitude, character, and persistence of a vaccine-elicited immune responses to create an effective HIV vaccine candidate.