This article describes the use of poorly absorbed antibiotics for the treatment of traveler's diarrhea. Poorly absorbed oral antibiotics can deliver high concentrations of drug to the site of enteric infection with minimal risk of systemic adverse effects, toxicity, and drug interactions. Compared with systemically absorbed oral antibiotics, poorly absorbed oral antibiotics may be less associated with the pressure that leads to the development of bacterial resistance, because they do not affect bacteria outside the gastrointestinal tract. In clinical studies, poorly absorbed oral antibiotics, including aztreonam, bicozamycin, and rifaximin, were more effective than and as well tolerated as placebo; in particular, rifaximin was as effective as oral ciprofloxacin in reducing the duration of illness in traveler's diarrhea. More research is warranted to delineate the effects of poorly absorbed antibiotics in invasive infection and to assess the potential for the development of bacterial resistance.