Rifaximin is a poorly absorbed rifamycin drug with unique pharmacokinetic properties: bile solubility making it highly active against pathogenic and non-pathogenic bacterial flora in the bile-rich small bowel and low water solubility making it active only against highly susceptible bacteria, primarily anaerobes, in the aqueous colon. The drug has anti-inflammatory gut mucosal stabilization properties that are important to its sustained effects in non-infectious diseases. Rifaximin is used chronically or recurrently for hepatic encephalopathy and diarrhea-predominant irritable bowel syndrome. Monitoring of long-term use of rifaximin for development of resistance and then determining whether developed resistance is associated with reduced efficacy are needed. Studies of changes of intestinal flora during therapy and the health implications of these changes are also needed.