Accumulating data in human immunodeficiency virus (HIV)-infected individuals support the hypothesis that in primary human immunodeficiency virus type 1 (HIV-1) isolates of different clades and phenotype (syncytium inducing [SI] and nonsyncytium inducing [NSI]) common antigenic structures must exist that can stimulate the immune response to produce a broad spectrum (cross-clade and cross SI and NSI) neutralization response. Certain vaccination regimens in chimpanzees and human volunteers with clade B SI type HIV-1 derived candidate vaccines induce neutralizing antibodies against intraclade B SI type primary HIV-1 isolates, but not against intraclade B NSI type of viruses. To be effective against the full antigenic spectrum of primary HIV-1 isolates (cross-clade--SI and NSI) candidate vaccines should contain immunogens of primary isolates representative of the whole antigenic spectrum of HIV-1. There is an urgent need to identify these immunogens and to improve their immunogenicity. As long as we have not yet characterized these cross-HIV-1 spectrum conserved immunogens, candidate vaccines against the more prevalent clades C, A, and E should be developed for evaluation in developing countries. In support of the follow-up and evaluation of the hopefully increasing number of phase 1, 2, and 3 HIV-1 vaccine trials in humans, it is considered a high priority to develop a high throughput neutralization assay, to further expand the use of a limited number of key primary HIV-1 isolates as a surrogate for neutralization of the entire HIV-1 antigenic spectrum (cross-clade--SI and NSI), to develop high throughput subtyping as well as a rapid system to monitor the immunogenic relatedness of different HIV-1 clades.