Despite this antigenic diversity of HIV-1, serum antibodies from some HIV-1-infected subjects can neutralize heterologous viral isolates, including isolates belonging to distinct genetic subtypes. A detailed analysis of these cross-neutralizing sera has begun to elucidate the antibody specificities that contribute to virus neutralization. In some sera, neutralization is achieved by a response to a functionally conserved viral epitope, such as the CD4 binding site of gp120. In other sera, antibodies to several epitopes on gp120 and gp41, including epitopes not yet well defined, appear to contribute to the overall serum neutralization. It is clear that conserved neutralizing epitopes are immunogenic during natural HIV-1 infection and further understanding of these epitopes can help guide the design of new vaccine candidates to elicit protective antibodies.