Infections caused by Streptococcus pneumoniae place a considerable personal and economic burden on both patients and healthcare systems. As the resistance of S. pneumoniae to older antimicrobial agents such as penicillin, cephalosporins, and macrolides has increased, new antimicrobials with good activity against S. pneumoniae have been developed. The newer fluoroquinolones, including levofloxacin, gatifloxacin and moxifloxacin provide a safe and easy tool in the treatment of S. pneumoniae infections. However, there have been recent reports of levofloxacin-resistant strains of S. pneumoniae. Pharmacokinetics and pharmacodynamics can be used to determine which fluoroquinolone delivers the best coverage against S. pneumoniae, and also the 24-h AUC/MIC ratio (the AUIC) required to impede the emergence of bacterial resistance. Monte Carlo analysis suggests that moxifloxacin, with 4-8-fold greater activity and higher AUIC against S. pneumoniae than levofloxacin or gatifloxacin, provides the best coverage in terms of probability of cure and probability of minimizing emergence of resistance.