Since 1989, strains of Salmonella typhi resistant to chloramphenicol, ampicillin, and trimethoprim (i.e., multidrug-resistant [MDR] strains) have been responsible for numerous outbreaks in countries in the Indian subcontinent, Southeast Asia, and Africa. MDR strains have also been isolated with increasing frequency from immigrant workers in countries in the Arabian Gulf, as well as in developed countries from returning travelers. In all MDR strains so far examined, multiple resistance has been encoded by plasmids of the H1 incompatibility group. As a result of the widespread dissemination of such strains, chloramphenicol can no longer be regarded as the first-line drug for typhoid fever. Because strains are also resistant to ampicillin and trimethoprim, the efficacy of these antibiotics has also been impaired, and ciprofloxacin is now the drug of choice for typhoid fever. Chromosomally encoded resistance to ciprofloxacin has now been observed in a small number of strains isolated in the United Kingdom from patients returning from the Indian subcontinent, and in at least one case the patient did not respond to treatment with this antibiotic. It is regrettable that resistance to ciprofloxacin has now emerged in MDR S. typhi, and it is of paramount importance to limit the unnecessary use of this vital drug so that its efficacy should not be further jeopardized.