It has been more than 25 years since HIV-1 was identified as the etiological agent for acquired immunodeficiency syndrome. The early optimism has turned into anxiety that we may not be able to develop a vaccine to contain this pandemic that has killed more than 25 million people. Conventional vaccine design to induce robust adaptive immunity have largely failed owing to some characteristics of HIV-1, including the extreme genetic variability in circulating viral isolates, ability to evade immune attack, and a high mutation rate that allows for rapid escape from adaptive immune responses. Nevertheless, recent success in protection against AIDS viruses in animal models and control of HIV in humans under certain circumstances shed a light on the future. Better understanding of disease pathogenesis and learning from SIV infection of primates may provide a path to continue the pursuit of an effective AIDS vaccine to contain the global epidemic.