One major obstacle to the design of a global HIV-1 vaccine is viral diversity. Presently, data suggest that a single antigen will not suffice to generate broadly reactive neutralizing antibodies to protect all individuals against all subtypes of HIV-1 infection. While some of the neutralizing epitopes are identified in the constant regions of the HIV-1 envelope (Env) glycoprotein, many are localized to variable regions and differ conformationally from one virus to the next. The successes of polyvalent vaccine approaches against other antigenically variable pathogens encourage adoption of the same approach for HIV-1 vaccine design. The critical question is which envelope antigens should be combined in a vaccine cocktail to provide maximum protection against HIV-1. A review of the existing human vaccines based on the polyvalent principle is included here to provide a historical perspective for the current effort of developing a polyvalent HIV-1 vaccine. Data generated from several groups actively working on candidate polyvalent HIV-1 vaccines are summarized. Information presented in this review highlights the potential and importance of the polyvalent vaccine approach for the future development of an effective HIV-1 vaccine.