New fluoroquinolones and fluoronaphthyridones continue to provide the mainstay of antibiotic development, despite recent events associated with unexpected or uncharacteristically severe adverse drug reactions. These have included hepatotoxicity caused by trovafloxacin (suspended), cardiotoxicity associated with grepafloxacin, and phototoxicity caused by clinafloxacin (both withdrawn). Prolongation of the QT interval appears to be an emergent class effect, the implications of which are not yet fully understood. However, the second-generation agents ciprofloxacin and, latterly, levofloxacin have excellent safety profiles and provide standard optimal choices for therapy of a wide range of gram-negative pathogens. They are also useful for many respiratory infections, though the use of ciprofloxacin in pneumococcal pneumonia has been questioned and continued use of levofloxacin may act as a selection pressure for emergence of quinolone-resistant Streptococcus pneumoniae. Active conservation measures may be required to protect the class from this problem because alternatives, should high-level penicillin-resistance continue to spread, are few. The new 8-methoxy quinolones (moxifloxacin and gatifloxacin) are more highly potent against both penicillin-susceptible and multidrug-resistant S. pneumoniae, while retaining activity against enterobacteria. Clinical Phase III development has shown them to produce very satisfactory clinical and bacteriologic responses in respiratory infections and to be remarkably free of clinically significant adverse effects. Postmarketing surveillance of moxifloxacin in Germany has revealed no additional concerns. These agents are now licensed in many countries, including the United States, and add a further, broad-based respiratory dimension to the future of the class.