A major focus of HIV-1 vaccine development has been directed towards a limited number of broadly conserved epitopes in the Envelope (Env) proteins that are sensitive neutralization targets in many primary isolates. However, evidence suggests that these epitopes are poorly immunogenic; similar antibodies are rarely produced by infected subjects, nor are they induced by various immunogens designed to express these epitopes. On the other hand, the major variable domains of Env are highly immunogenic; antibodies against these regions are common in sera of infected patients and easily generated upon immunization. Although these epitopes are extremely sensitive neutralization targets in some laboratory strains and primary isolates, the neutralization range of antibodies against these sites is limited. This review describes potent neutralization epitopes located in the variable regions of Env and discusses the bases for the limited neutralization breadth of antibodies against these targets. Strategies are discussed for using available information to design immunogens capable of exploiting the potential of these regions as vaccine targets.