More than 30 years after the discovery of the human immunodeficiency virus as the agent that causes AIDS, an effective vaccine against this deadly disease has yet to be developed. The pathway to the development of a vaccine has been riddled with challenges, many unique to HIV itself. As a result, advocates, scientists, and funders have had to move away from a “home run” philosophy that had anticipated early success. Nonetheless, much has been learned along the way about the genetic diversity of the virus, the limitations of animal studies, and the cultural infra structure and regulatory challenges involved in testing HIV vaccines. The application of coordinated approaches to face the difficulties outlined in this article is a logical way forward in developing a vaccine. Then even more progress can be made, in spite of all the uncertainties, toward the achievement of a successful vaccine.