We assessed antibiotic resistance in Streptococcus pneumoniae collected worldwide in 2003. Resistance to clarithromycin was the highest overall (34.1%) followed by penicillin G (22.1%). Patient age and/or country of origin had the greatest effect on susceptibility. Resistance was highest in children<6 years of age and in patients from South Africa or France. Resistance to penicillin or amoxicillin/clavulanic acid decreased in adults and was low in Germany. Fluoroquinolone resistance was very low overall, but 3.0% levofloxacin resistance (2.6% gatifloxacin and 0.4% moxifloxacin) was observed in Italy. Interestingly, many isolates with minimum inhibitory concentrations (MICs) at the top of the fluoroquinolone susceptibility breakpoints possessed single quinolone resistance-determining region (QRDR) mutations. Care should be taken when treating fluoroquinolone-susceptible isolates with a higher MIC, which are likely to harbour QRDR mutations and may become fully resistant and cause treatment failure. We concur with the conclusions of other recent studies that suggest fluoroquinolone breakpoints should be lowered to ensure these isolates are categorised as resistant. Fluoroquinolones would still remain an important alternative treatment for respiratory tract infections (albeit for adults only), with moxifloxacin being the most potent fluoroquinolone tested in this study.