This chapter reviews the vaccines against four prominent and prototypical respiratory mucosal bacteria-. Corynebacterium diphtheriae, Bordetella pertussis, Haemophilus influenzae, and Streptococcus pneumonia. The chapterhighlights the virulence mechanisms involved in the mucosal infections that form the basis for these immunogenic and clinically efficacious vaccines. S. pneumoniae is the single most common cause of potentially preventable respiratory bacterial disease in children and adults worldwide. Systemic immunization is effective in preventing localized respiratory bacterial infections with C. diphtheriae and B. pertussis and both invasive infections and colonization with H. influenzae. Diphtheria vaccine is directed towards a single but pivotal disease-related toxin. The H. influenzae vaccine is directed towards a single prominent virulence mechanism-the polysaccharide capsule, but towards only one capsule (type b) on a complement-lysis-sensitive gram-negative organism. In contrast, S. pneumoniae has no preeminent single disease-determining toxin, and the efficient killing of this gram-positive complement lysis-resistant organism requires the combination of complement, phagocytic cells, and specific antibody to many capsular polysaccharides. © 2005 Elsevier Inc. All rights reserved.