PURPOSE OF THE REVIEW: This manuscript reviews the recent literature related to new developments in the understanding of existing and novel virulence factors of the pneumococcus that are of potential importance in the development of novel preventive and therapeutic strategies. RECENT FINDINGS: The pneumococcal capsule and pneumolysin have long been recognized as being two of the most prominent virulence factors, with much recent research having revealed previously unrecognized mechanisms by which they contribute to the pathogenesis of infection. Although the pneumococcal capsule has been considered a sine qua non for virulence, the emergence of pathogenic nonencapsulated strains with newly recognized virulence determinants has also been described. Not unexpectedly, but of concern, nonencapsulated strains are unaffected by current pneumococcal vaccines. This, together with the finding of novel virulence factors, as well as new mechanisms of pathogenicity of established virulence determinants, underscores the resilience of the pneumococcus in confronting challenges in its environment, most importantly those posed by antibiotics and vaccines. SUMMARY: Recent advances in the understanding of pneumococcal virulence factors provide potential opportunities for the development of novel putative therapeutic or preventive strategies.