Recent insights into the immunopathogenesis of pneumococcal infection, a common and significant cause of morbidity and mortality, have implicated pneumolysin as being a prominent virulence factor, which may play a role in microbial colonization, invasion and dissemination, as well as tissue inflammation. Being a highly immunogenic polypeptide produced by all clinically relevant pneumococcal isolates, pneumolysin is recognized as a potential carrier protein for polysaccharide conjugate vaccines, while in the setting of acute disease, promising pneumolysin-directed pharmacological strategies include, among others, macrolides and corticosteroids.