The goal of vaccination is to establish long‐term immunological readiness that allows rapid protection against infectious disease. All current successful vaccines achieve this by inducing neutralizing antibodies, which are effective against acute, cytopathic infections that could otherwise prove fatal. By contrast, potential vaccines against highly variable pathogens that establish persistent infections, such as HIV, have been unsuccessful, as responses in addition to neutralizing antibodies, directed to specific anatomical locations, are probably necessary. Human studies on human immunovirus (HIV)‐exposed/infected long‐term nonprogressors to acquired immunodeficiency syndrome (AIDS) are beginning to reveal the correlates of immune protection that new vaccines should attempt to reproduce. Coupled with exciting new vaccine design and delivery strategies, these novel HIV vaccine approaches offer real hope that the HIV/AIDS pandemic can finally be overcome.