Macrolides are currently recommended as first-line agents for the empirical treatment of community-acquired pneumonia. Heavy use of these agents for a variety of indications has resulted in an increasing incidence of macrolide resistance among pneumococcal isolates. Although several case reports and small case series have suggested that in vitro macrolide resistance is associated with treatment failure in cases of pneumococcal pneumonia, other observational data suggest that drug susceptibility testing may not correlate with treatment failure. In this article, we review current information on the mechanisms of macrolide resistance and the pharmacodynamics of macrolide therapy, together with efficacy data from animal models and clinical observations, to begin to gauge the clinical significance of macrolide resistance in Streptococcus pneumoniae. Areas for further investigation are highlighted.