The number-1 indication for antibiotic prescriptions in the United States is a respiratory tract infection. The changing spectrum of pathogens and emerging bacterial resistance are changing the way these infections are managed. The epidemiology of community-acquired pneumonia has changed significantly in the past 20 years, with increased diversity of pathogens and mortality. Emerging resistance in respiratory tract pathogens, particularly to beta-lactams, is an increasing concern. Of the important gram-negative pathogens, more than a third of Haemophilus influenzae isolates are now resistant to beta-lactam antibiotics, as well as virtually all isolates of Moraxella catarrhalis. Of the gram-positive organisms, more than 40% of Streptococcus pneumoniae isolates are no longer susceptible to penicillin, and methicillin resistance has been reported in up to half of Staphylococcus aureus isolates in some institutions. Among staphylococci, resistance to the beta-lactam methicillin is often accompanied by resistance to multiple classes of antibiotics, particularly the macrolides. Little resistance to fluoroquinolones has been reported among gram-negative respiratory tract pathogens and S pneumoniae, although increasing resistance may be seen as these drugs are used with increasing frequency. In contrast, fluoroquinolone resistance can develop rapidly in S aureus and appears to be associated with methicillin resistance. Fortunately, many of the newer fluoroquinolones appear to offer significant activity against methicillin-resistant S aureus isolates and are active against ciprofloxacin-resistant strains of S pneumoniae. Today, to combat respiratory tract infections, a broad-based empiric therapy needs to be used and bacterial resistance must be taken into account. New antimicrobial options must be considered, with an emphasis on effective drug use and optimal dosing. Even if a direct relationship between antibiotic resistance and clinical outcomes in the treatment of pneumonia in adults has not been extensively demonstrated, the increasing problem of resistance has changed treatment approaches for respiratory tract infections as a whole.