Multi-drug resistant Gram-positive cocci have emerged as significant pathogens of community- and hospital-acquired infections. Several antimicrobial agents that can be used for the treatment of these infections are presently available. However, the most appropriate treatment for each infection has not been established. Linezolid seems to be a promising choice. Linezolid is bactericidal against Streptococci and bacteriostatic against Enterococci and Staphylococci. It has excellent pharmacokinetic and pharmacodynamic profiles, which allow early change from intravenous to oral administration. In addition, its effectiveness for the treatment of Gram-positive infections in immunocompetent and immunodeficient patients have been studied in several randomized controlled trials. In this review, the authors summarize all the available evidence regarding the effectiveness and safety of linezolid compared with other antimicrobial agents for its approved and off-label indications.