Successes for neutralizing antibodies (nAbs) against the human immunodeficiency virus (HIV) include potent cross-clade neutralization of primary virus isolates by human neutralizing monoclonal antibodies (nmAbs) targeting conserved envelope epitopes. Furthermore, passively administered combinations of human nmAbs prevented infection in primates, indicating that epitopes recognized by such nmAbs are key determinants for protection. Lastly, in the absence of CD8+ T cells, nAbs may act as a second line of defense during chronic infection. Taken together, these results argue for generating nAb response-based prophylactic and/or therapeutic AIDS vaccines. We suggest that the epitopes identified by passive immunization represent excellent targets for the rational design of nAb response-based AIDS vaccines.