The fluoroquinolone class of antibacterial agents are among the most frequently prescribed drugs, with utility in a broad range of bacterial infections. Although very useful agents, the fluoroquinolones as a class are associated with a number of adverse events, some with considerable clinical significance. In the past 15-20 years, tolerability concerns have led to restrictions on the use of the fluoroquinolones and, in some instances, the withdrawal of agents from the market. This review focuses on the safety and tolerability of levofloxacin, a third-generation fluoroquinolone, relative to other fluoroquinolones. A literature search was performed of the MEDLINE database encompassing the dates 1980-2009, using as keywords the drug names levofloxacin and concurrently marketed fluoroquinolones combined with the words 'safety', 'adverse effect' or 'adverse drug reaction', or the name of the specific adverse effect. Adverse events commonly associated with the fluoroquinolones include gastrointestinal and CNS toxicity (most frequently headache and dizziness), as well as other adverse events including ECG abnormalities (for example QT interval prolongation), disrupted glucose metabolism, phototoxicity, tendon and joint disorders, hypersensitivity and skin disorders, and hepatic toxicity. Package inserts for the fluoroquinolones in Europe and the US contain warnings regarding these risks. US package inserts also carry 'black-box' warnings regarding the risk of tendon rupture and joint disorders with these agents; however, there is a substantial body of evidence to indicate that there are marked differences in the tolerability profiles of the individual agents within the fluoroquinolone class. These differences may be explained, at least in part, by structural differences: all fluoroquinolones share a basic quinolone core, with differences in specific side chains underlying the adverse event relationships. Furthermore, many of the fluoroquinolone-associated adverse effects and toxicities occur more frequently in patients with pre-existing risk factors, or in certain subpopulations. Notably, package inserts for the fluoroquinolones carry warnings regarding use in the elderly, paediatric patients and patients with pre-existing, or factors predisposing to, seizure disorders. Because of this, many adverse reactions with these agents could be prevented by improving patient screening and education. The recent withdrawal of gatifloxacin due to dysglycaemia makes it timely to review the safety and tolerability of the individual agents in this class. Overall, it appears that levofloxacin is relatively well tolerated, with low rates of clinically important adverse events such as CNS toxicity, cardiovascular toxicity and dysglycaemia.