Certain human pathogens avoid elimination by our immune system by rapidly mutating the surface protein sites targeted by antibody responses, and consequently they tend to be problematic for vaccine development. The behavior described is prominent for a subset of viruses—the highly antigenically diverse viruses—which include HIV, influenza, and hepatitis C viruses. However, these viruses do harbor highly conserved exposed sites, usually associated with function, which can be targeted by broadly neutralizing antibodies. Until recently, not many such antibodies were known, but advances in the field have enabled increasing numbers to be identified. Molecular characterizations of the antibodies and, most importantly, of the sites of vulnerability that they recognize give hope for the discovery of new vaccines and drugs.