Morbidity and mortality due to certain bacterial pathogens have not declined despite the availability of effective antimicrobial treatments. Staphylococcus aureus and Streptococcus pyogenes cause a number of serious infections, such as necrotizing fasciitis and toxic shock syndrome, which are associated with the release of bacterial toxins. Animal studies have demonstrated clindamycin, a protein synthesis inhibitor, to be more effective in treating these severe infections than other more susceptible antimicrobial treatments. Linezolid, another protein synthesis inhibitor, also has shown efficacy in in vitro studies. Human trials to validate the effects of antibiotic therapies on bacterial virulence have not been performed. Future animal and human studies are needed to help elucidate the immunomodulatory mechanisms of protein synthesis inhibitors in order to optimize antimicrobial treatment and decrease the morbidity and mortality associated with severe bacterial infections.