The discovery of nalidixic acid in 1962, and its introduction for clinical use in 1967, marks the beginning of five decades of quinolone development and use. It was not until the discovery and licensing of the fluoroquinolones in the 1970s and 1980s that these drugs began to establish their place in the armamentarium of clinically useful antimicrobials. At the beginning of the 21st century, in their fifth decade of discovery and use, our understanding of structure-function relationships has improved, and better compounds, in terms of both spectrum of antimicrobial cover and pharmacokinetics, have been developed. The clinical utility of this expanding class of antimicrobial agents, and the lower propensity for the development of resistance with the "newer" fluoroquinolones will need to be continually monitored in the changing therapeutic environment. Antibiotic drug choice will remain difficult in the presence of increasing resistance, but the introduction of the new fluoroquinolones has created a new and exciting era in antimicrobial treatment. The role of these agents has already been acknowledged in a number of clinical guidelines, and appropriate use of these agents may help to preserve their clinical utility, enabling them to realize their full therapeutic potential.