Streptococcus pneumoniae is one of the major bacteria cause of respiratory tract infections and colonises the nasopharyngeal cells of asymptomatically healthy individuals. The development of disease condition is often preceded by nasopharyngeal colonisation. In susceptible individuals such as children less than 2 years, the elderly above 65 years, and the immunocompromised, the pneumococci may disseminate and cause life-threatening disease, including causing otitis media, pneumonia, bacteraemia/sepsis and meningitis. Report shows that approximately 1 million children less than 5 years of age die annually in developing countries from pneumococcal disease. The treatment of pneumococcal infections has been complicated by rising trend of antibiotic resistance. Several studies shows that global prevalence of penicillin-resistant and macrolide-resistant Streptococcus pneumoniae varies between 18.2% to 22.1% and 24.6% to 31.8% respectively. Current prevention strategies include the use of pneumococcal polysaccharide vaccines and conjugates vaccines. The capsular polysaccharide vaccines are antibody dependent and are poorly immunogenic in the target groups and also does not elicit immunologic memory. In contrast, the conjugate vaccines have shown high efficacy, but limited as they only provide protection against the capsular serotypes/groups present in the vaccine resulting to capsular switch in types not incorporated in the conjugate vaccines. However, recent advances in the understanding of the structure and function of various pathogenicity and virulence factors have paved way for the possibility of developing protein vaccines. This review focuses on pneumococcal virulence factors and the potential targets for protein-based pneumococcal vaccine production. KEY WORDS: Streptococcus pneumoniae, Capsular polysaccharide vaccines, conjugate vaccines, protein-based pneumococcal vaccines, virulence factors.