Many of the critical features of the neutralizing antibody response to HIV and SIV infection have yet to be elucidated. It is not known to what extent the primary neutralizing antibody response of the host is directed at linear versus complex epitopes or to V3 versus non-V3 determinants. Neutralization escape mutants appear to arise during the course of infection of single individuals, but the variable regions primarily responsible for this escape have not been defined. Most importantly, we do not know the full impact of the emergence of neutralization-resistant variants on the maintenance of persistent infection and the evolution of the chronic disease course. In this review we summarize the evidence for immune selection of escape mutants among the more primitive ungulate lentiviruses and discuss corresponding information in SIV and HIV primate systems. In doing this, we describe the nature of sequence variation in SI V and HIV envelope and discuss the selective forces which may be driving sequence change in each of the variable domains. Despite gaps in existing knowledge, we conclude that neutralizing antibodies are important in limiting HIV and SIV replication in vivo. Specific selection of sequence variants that are resistant to neutralization argues strongly that neutralizing antibodies do serve to limit HIV and SIV replication during the lengthy asymptomatic stage of infection.