Since the early 1960s, considerable advancements have been made to standardize and provide quality assurance for clinical susceptibility testing procedures of antimicrobial agents. Controversy, however, remains as to the interpretation of clinical laboratory susceptibility test results. While some feel susceptibility breakpoints should only detect resistance mechanisms, others believe they should predict a high probability of clinical response. This has resulted in confusion among clinicians, as it has been apparent for some time that there can be discordance between interpretive test results and clinical response to therapy (generally cures of infections caused by resistant pathogens). Nearly simultaneous with the beginning of the standardization process for clinical susceptibility testing procedures, the first penicillin-resistant Streptococcus pneumoniae isolates were detected. During the ensuing decades, penicillin-resistant pneumococci became a greater clinical concern, resulting in macrolides emerging as safe therapeutic alternatives to beta-lactam agents for the treatment of community-acquired respiratory tract infections. During the last 10 years, the incidence of pneumococcal isolates with elevated macrolide minimum inhibitory concentration (MIC) values has also increased, yet the debate over the clinical meaning of these statistics persists. The youthful science of pharmacokinetics-pharmacodynamics provides a useful platform to determine which pneumococcal strains with elevated MIC values can be treated with contemporary dosing regimens and also facilitates the proper selection of antimicrobial breakpoints for all antimicrobial classes, including the newer macrolides.