Antibiotic resistance has become a major problem in the treatment of gram-positive bacterial infections. These organisms are able to escape antibiotic activity through several mechanisms including beta-lactamase production, altered penicillin-binding proteins, aminoglycoside-modifying enzymes, modification of the target site of the antibiotic, and active efflux. Resistant determinants may be carried on the chromosome, and are transmitted vertically by clonal dissemination, or on mobile elements such as plasmids, transposons or integrons capable of horizontal transfer both within and between species. Several resistant genes can be inserted in a given integron, resulting in multi-drug resistance. Antimicrobial resistance mechanisms can be caused or induced following the widespread use of antibiotics. The most important gram-positive resistant organisms include penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus with intermediate resistance to vancomycin, and enterococcal strains that express high-level resistance to aminoglycosides and/or resistance to vancomycin. In several instances, these strains show multi-drug resistance and cannot be treated with currently available agents. Therapeutic strategies include the use of a higher antibiotic dosage, the use of alternative, non-conventional drugs, alone or in combination, after demonstration of their efficacy in vitro and in experimental animal models, and the development of new drugs. New agents available include quinupristin/dalfopristin and line-zolid with activity against most resistant gram-positive bacteria. Promising new drugs that may reach the market in the near future include daptomycin and oritavancin. Careful use of antibiotics and adherence to infection control standards are crucial in preventing the development and the spread of resistant organisms.