Although the fluoroquinolones are presently used to treat tuberculosis primarily in cases involving resistance or intolerance to first-line antituberculosis therapy, these drugs are potential first-line agents and are under study for this indication. However, there is concern about the development of fluoroquinolone resistance in Mycobacterium tuberculosis, particularly when administered as monotherapy or as the only active agent in a failing multidrug regimen. Treatment failures as well as relapses have been documented under such conditions. With increasing numbers of fluoroquinolone prescriptions and the expanded use of these broad-spectrum agents for many infections, the selective pressure of fluoroquinolone use results in the ready emergence of fluoroquinolone resistance in a diversity of organisms, including M tuberculosis. Among M tuberculosis, resistance is emerging and may herald a significant future threat to the long-term clinical utility of fluoroquinolones. Discussion and education regarding appropriate use are necessary to preserve the effectiveness of this antibiotic class against the hazard of growing resistance.