The increasing resistance of Streptococcus pneumoniae, the most important community respiratory pathogen, to beta-lactams and other first-line antimicrobial agents usually employed for the empirical treatment of lower respiratory tract infections has led to the inclusion, in several current guidelines, of a fluoroquinolone with improved activity against pneumococci as the first choice agent for the management of such infections. The excellent microbiological, pharmacokinetic, and pharmacodynamic characteristics of the new fluoroquinolones (levofloxacin, moxifloxacin, gemifloxacin, and gatifloxacin) have encouraged their growing use, probably contributing to the emergence of fluoroquinolone-resistant pneumococci; although pneumococcal resistance to new fluoroquinolones is currently low, there is still concern about the potential for widespread emergence of resistance to these agents if they become indiscriminately used. Levofloxacin clinical failures have already been reported in the management of patients with pneumococcal community-acquired pneumonia; development of resistance in clinical isolates of S. pneumoniae has prompted a critical reexamination of the newer fluoroquinolones to assess their potency and to preserve their activity. An understanding of the pharmacokinetic and pharmacodynamic properties, allowing selection of the most potent fluoroquinolone, will reduce the opportunity for resistance to develop. Finally, a targeted use of these agents will maintain class efficacy.