After 25 years of use in the United States, trimethoprim-sulfamethoxazole (TMP-SMX) is widely prescribed for various indications. By virtue of sequential blockade of microbial folic acid synthesis, the antimicrobial combination has excellent in vitro inhibitory activity against many common respiratory and urinary tract pathogens, as well as many nosocomial infecting strains. In patients infected with the human immunodeficiency virus, TMP-SMX provides prophylactic and therapeutic potency against Pneumocystis carinii but at the risk of frequent side effects. TMP-SMX is also used for treatment of pulmonary and disseminated nocardiosis and some forms of Wegener's granulomatosis, as well as for prophylaxis of spontaneous bacterial peritonitis. Increasing bacterial resistance and concern about occasional severe adverse effects suggest that the usefulness of TMP-SMX may diminish in the future.