Travelers’ diarrhea is a common illness among international travelers from developed to developing countries. Travelers’ diarrhea is caused by ingestion of contaminated food and water. Bacteria are the primary cause of travelers’ diarrhea. In most surveys, the most common diarrheal pathogen identified is enterotoxigenic Escherichia coli. There are several antimicrobial agents available for the treatment of travelers’ diarrhea including rifaximin which is approved in the United States for the treatment of travelers’ diarrhea due to noninvasive E. coli strains. In this review, we will review the most recent advances of rifaximin for the treatment and prevention of travelers’ diarrhea, with regard to its pharmacokinetics, in vitro susceptibility profile, and efficacy and safety data from clinical trials.