Burgeoning resistance to antibiotics among common respiratory pathogens poses a very real risk to public health. A need therefore exists for new antibiotics that not only target all common respiratory pathogens, including problematic strains such as penicillin- and macrolide-resistant Streptococcus pneumoniae, but also resist resistance. The ketolides are a new class of antibiotics, of which telithromycin is the first to undergo clinical evaluation, designed to address such issues. These agents possess several innovative structural modifications that not only confer activity against common respiratory pathogens, irrespective of their beta-lactam or macrolide susceptibility, but also minimize the risk of emergent resistance. Ketolides such as telithromycin therefore represent important new options for the empiric treatment of community-acquired respiratory tract infections in an era of increasing resistance. They may be especially useful in areas where macrolide resistance among S. pneumoniae is common because current macrolide treatments against such pathogens are far from optimal.