Linezolid has demonstrated activity against antibiotic-susceptible and antibiotic-resistant aerobic Gram-positive cocci. The availability of intravenous and oral formulations, with near 100% bioavailability of the latter, is hoped to facilitate the management of multiply drug-resistant Gram-positive infections. Linezolid was approved for clinical use in the United States in April 2000 and has subsequently been approved in other countries for the management of community-acquired and nosocomial pneumonia, complicated and uncomplicated skin and soft-tissue infections, and infections caused by methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, including cases with concurrent bacteremia. Additional studies have demonstrated potential use in febrile cancer patients with neutropenia, and case reports have documented some efficacy in the management of infective endocarditis, tuberculosis, nocardiosis, and in anaerobic infections. Given the potential for significantly increased use of linezolid, a thorough review and update of its tolerability and safety profile is warranted.