Recent surveillance studies suggest that the incidence of resistance to macrolide antibiotics in common community-acquired respiratory tract pathogens, particularly Streptococcus pneumoniae and Streptococcus pyogenes, is increasing and limiting the usefulness of these drugs. The ketolides, of which telithromycin is the first to be available for clinical use (but not yet in the United States), represent a new class of antibacterials developed specifically to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides possess innovative structural modifications, a 3-keto group and a large N-substituted C11, C12-carbamate side chain. This novel structure allows ketolides, which are inhibitors of protein synthesis, to exert a more effective interaction with domain II of the 23S rRNA, enhancing binding to bacterial ribosomes and allowing binding to macrolide-lincosamide-streptogramin B-resistant ribosomes. This novel chemical structure also promotes greater stability of telithromycin in acid conditions, providing the potential for greater stability in gastric fluid and at cellular/tissue levels. Early clinical trials support the bacteriologic and clinical efficacy of telithromycin in the treatment of upper respiratory tract infections (RTIs) such as streptococcal pharyngitis and acute sinusitis, including infections caused by macrolide-resistant S. pneumoniae and S. pyogenes. Common adverse side effects associated with telithromycin are predominantly gastrointestinal, usually of mild to moderate severity, and rarely involve withdrawal of the drug. Telithromycin represents an attractive option for the empiric treatment of upper RTIs, especially as resistance to macrolides is likely to continue to increase.