Much of the current effort in HIV-1 vaccine design is directed at achieving T-cell immunity that will result in enough immunological memory to contain HIV-1 infection after acquisition. However, antigenic diversity, plus a lack of understanding of HIV-1 vaccine immunology, have hindered the development of a globally effective cytotoxic T-lymphocyte (CTL)-based vaccine. Cellular response, in using a finite immune system to recognize an infinite number of potential pathogens, exhibits a series of parsimonious features. These features are considered critical in modulating HIV-1 vaccine multiple specificities. We took the features into consideration when the potential epitope coverage (E(c)) to circulating strains by current vaccine strategies was analyzed. Based on these analyses, several approaches are proposed to enhance the breadth of vaccine responses and, hence, the potential protective efficacy.