Gram-positive organisms are continually a major cause of infection. These organisms are ever-evolving and exhibit resistance to nearly all available agents. Historically, vancomycin was crowned the drug of choice for many of these organisms including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and penicillin-resistant Enterococcus spp. Many of these organisms have exhibited reduced susceptibility or frank resistance to vancomycin which has resulted in treatment failure. For this reason, new strategies in treating Gram-positive infections are a hot topic. There are two general approaches to waging this war: i) development of new antimicrobial agents; and ii) reinvigorating old antibiotics that still retain appreciable activity against Gram-positives. We review both antibiotic groupings with a focus on S. aureus, S. pneumoniae and Enterococcus spp.