Vaccines exist to protect children and adults from pneumococcal infection. The adult vaccine contains capsular polysaccharides from those pneumococci causing the vast majority of pneumococcal infection around the world. This vaccine is, however, poorly immunogenic and not as protective as would be desired. The vaccine for children is a seven-valent conjugate vaccine, which is highly protective against invasive infection and offers some protection against otitis media and pneumococcal carriage. The capsular types in the vaccine are not all appropriate for the developing world and the vaccine is too expensive for use in the developing world. As a result of these problems there have been extensive efforts to develop pneumococcal vaccines for adults and children based on cross-reactive protein antigens. The molecules used are in general virulence factors and the antibodies to them neutralize their function, thus reducing the virulence of the infecting bacteria. Studies in humans have revealed that the proteins studied are invariably immunogenic in humans, as at least low levels of antibody are seen following colonization or infection. Studies in mice have demonstrated that vaccines containing more than one of these virulence proteins are generally more protective than those involving just one. Proteins that have been studied the most in mice are pneumococcal surface protein A (PspA), PspC, PsaA, and pneumolysin. PspA has been used in human safety trials and was shown to elicit antibodies that can protect mice from otherwise fatal pneumococcal infections. © 2003 Published by Elsevier Ireland Ltd.