While they are very useful agents, fluoroquinolones (FQs) are associated with a number of serious adverse effects (AEs). The objective of this paper is to describe the characteristics of frequent serious AEs related to FQs along with their risk factors, their safety in specific populations, and the main drug-drug interactions that may occur. Serious AEs commonly associated with FQs include tendon disorders (particularly tendinopathy and tendon rupture), CNS toxicity (seizure and encephalopathy), peripheral neuropathy (including small fiber neuropathy), cardiovascular toxicity (QT interval prolongation, dissection, and aneurysm rupture), disrupted glucose metabolism, phototoxicity, C. difficile infections, acute renal failure, and hepatic toxicity. Most of these AEs are common to all FQs, but some, such as acute kidney failure on crystallization with ciprofloxacin or norfloxacin, are more specific. Unlike the AEs associated with most other antibiotics, some of these AEs (e.g. tendinopathy or neuropathy) may occur after FQ discontinuation, and others may subsequently progress (e.g. FQ-associated disability). The risk of serious AE is heightened by factors having to do with patient age and comorbidities, the characteristics of the FQ treatment (dose and/or duration) and associated drug intake. To conclude, FQs appear to be associated with a higher risk of serious AEs than most of the other antibiotics available for the same indications, however some AEs can be avoided by bearing in mind the predisposing risk factors.