The need for a safe, effective and affordable HIV vaccine has never been greater. In 2004 almost five million people became infected with HIV. In addition, providing access to antiretrovirals in Africa remains a huge challenge. A successful vaccine against HIV will probably need to stimulate the innate immune system, generate high levels of neutralizing antibodies, induce strong cellular immune responses and mucosal immunity, and should induce broad-spectrum immunity able to cover all HIV subtypes. In this review, we describe the limitations and challenges of developing a safe and effective HIV vaccine. We also emphasize possible approaches for overcoming immune escape in HIV infection, the lessons learned from the clinical trials of HIV-1 candidate vaccines, and the most important scientific highlights of the Keystone 2005 Symposium. When an effective vaccine is eventually found, we will face the enormous task of making it accessible to those who need it most.