Mucosal vaccination against pneumococcal disease offers potential protection against otitis media, pneumonia and invasive disease, including providing herd benefit by reducing pathogen carriage. The major obstacle, however, remains the lack of a suitable adjuvant for use in humans. Animal models have demonstrated success of interleukin-12 (IL-12) as an adjuvant for mucosal vaccines using recombinant pneumococcal protein antigens. This review examines the biology of the IL-12 cytokine family, the toxicity of IL-12 in human studies and suggests approaches by which IL-12 could be developed as a mucosal adjuvant with pneumococcal protein based vaccines, for use in humans. © 2008.