More focused research on a mucosal HIV-1 vaccine is needed urgently. An increasing amount of collected data, using heterologous multimodality prime-booster strategies, suggest that an efficient and protective HIV-1 vaccine must generate broad, long-lasting HIV-specific CD8(+) cytotoxic T-lymphocyte and neutralizing antibody responses. In the mucosa, these responses would be most effective if a preferential stimulus of HIV-1 neutralizing secretory immunoglobulin A and G were obtained. The attractive property of mucosal immunization is the obtained mucosal and systemic immunity, whereas systemic immunization induces a more limited immunity, predominantly in systemic sites. These objectives will require new vaccine regimens, such as multiclade HIV DNA and protein vaccines (nef, tat, gag and env expressed in DNA plasmids) delivered onto mucosal surfaces with needle-free delivery methods, such as nasal drop, as well as oral and rectal/vaginal delivery, and should merit clinical trials.