A quarter century of scientific discovery has been applied to developing an AIDS vaccine, yet this goal remains elusive. Specific characteristics of the virus, including the extreme genetic variability in circulating viral isolates worldwide, biological properties of HIV that impede immune attack, and a high mutation rate that allows for rapid escape from adaptive immune responses, render this a huge challenge. However, evidence of protection against AIDS viruses in animal models and control of HIV in humans under certain circumstances, together with scientific advances in understanding disease pathogenesis, provide a strong rationale and objective paths to continue the pursuit of an effective AIDS vaccine to stem the global epidemic.