A major obstacle to the design of a global HIV-1 vaccine is viral diversity. At present, data suggest that a vaccine comprising a single antigen will fail to generate broadly reactive B-cell and T-cell responses able to confer protection against the diverse isolates of HIV-1. While some B-cell and T-cell epitopes lie within the more conserved regions of HIV-1 proteins, many are localized to variable regions and differ from one virus to the next. Neutralizing B-cell responses may vary toward viruses with different i) antibody contact residues and/or ii) protein conformations while T-cell responses may vary toward viruses with different (i) T-cell receptor contact residues and/or (ii) amino acid sequences pertinent to antigen processing. Here we review previous and current strategies for HIV-1 vaccine development. We focus on studies at St. Jude Children's Research Hospital (SJCRH) dedicated to the development of an HIV-1 vaccine cocktail strategy. The SJCRH multi-vectored, multi-envelope vaccine has now been shown to elicit HIV-1-specific B- and T-cell functions with a diversity and durability that may be required to prevent HIV-1 infections in humans.