Fluoroquinolones are a class of antibiotics that are widely used in the treatment of a number of severe infections frequently observed in intensive care units (ICU). From a pharmacodynamic point of view, the optimal conditions for guaranteeing clinical recovery and preventing the occurrence of resistance to this class of antibiotics are represented by the ratios of C(max)/MIC > 12.2 and AUC(24h)/MIC equal to 100-125 hours for Gram-negative bacteria, and about 30-40 hours for Gram-positive cocci. Taking this into consideration, the pharmacokinetics and pharmacodynamics shown in healthy volunteers suggest that with the use of standard doses of the various fluoroquinolones, an optimal AUC(free)/MIC ratio for Gram-negative bacteria may be ensured with a minimum inhibitory concentration (MIC) < 0.25-0.5 mg/L and for Gram-positive bacteria with an MIC < 0.5-1 mg/L. The need to increase the dosage, or to combine them with other antibiotics is therefore recognized, when it is necessary to ensure adequate coverage of intermediately sensitive microorganisms (MIC 1-2 mg/L). In addition, patients recovered in the ICU often present some peculiar pathophysiological conditions that increase the distribution volume and/or the renal clearance of the drug. Thus it is likely that in this situation it would be reasonable to increase daily dosages, independent of the in vitro pattern of drug sensitivity (e.g. 500 mg b.i.d. for levofloxacin). Data from various clinical and pharmacological studies suggesting a potential role for fluoroquinolones both in monotherapy and combination therapy in the treatment of different clinically severe conditions are presented and discussed. This offers the dual opportunity to evaluate the role of quinolones as an alternative to aminoglycosides in combination with a beta-lactam and, at the same time, to consider their use in a periodic rotation program of anti-Gram-negative antibiotic therapy when there is a high risk of resistance selection, such as in the ICU. In conclusion, the role of fluoroquinolones in the treatment of multiple infectious diseases, such as bacteremia/sepsis, pneumonia and severe urinary tract infections in an environment such as the ICU is growing stronger, while there are convincing data indicating that these molecules might play a role in the treatment of meningitis in the near future.