The increasing resistance of S. pneumoniae to antimicrobial agents is a cause for concern. Although a number of therapeutic strategies are possible, local patterns of resistance must be considered. It is essential to determine the susceptibility of individual strains to penicillin and other antimicrobial agents that could be used for therapy. Communication between the clinician and the laboratory is vital to determine the best therapeutic options. The recent recognition of cephalosporin-resistant strains emphasizes the need to determine susceptibility to cephalosporins. Clinical laboratories should be aware of the recently proposed changes in the definition of cephalosporin resistance, and clinicians need to be aware of how these changes affect the choice of antibiotic therapy. Until pneumococcal disease can be effectively prevented, we can expect resistant pneumococcal infections to continue to pose therapeutic difficulties.