Pharmacokinetic drug-drug interactions occur when the absorption, metabolism, distribution, or elimination of one drug is altered by coadministration of another. Compared with many antimicrobial drugs, the fluoroquinolones cause relatively few pharmacokinetic drug-drug interactions. Absorption interactions are the most important, and the absorption of all fluoroquinolones is reduced when they are given with multivalent cations, including those frequently found in antacids such as aluminum, magnesium, and calcium. This chapter reviews fluoroquinolone pharmacokinetic drug-drug interactions, with an emphasis on newer agents, and discusses some remaining controversial issues. The current prescribing information for each fluoroquinolone should be consulted for the most recent drug-drug interaction information. Similar to the quinolone warfarin interaction, several early case reports suggested that quinolones may impair the metabolism of cyclosporine and promote nephrotoxicity. Though rifampin is one of the most potent inducers known of multiple P450 enzymes, there appears to be little effect on metabolism of most quinolones. Research has focused on the neuroinhibitory effects of quinolones, on gamma amino butyric acid receptors, central nervous system (CNS) adverse effects of the fluoroquinolones, and a possible pharmacodynamic interaction with certain nonsteroidal anti-inflammatory drugs (NSAIDs).