Irritable bowel syndrome (IBS), a chronic, nonfatal illness is commonly encountered in clinical practice; however, treatment options are limited and often ineffectual. Despite this, there is increasing evidence that bacterial overgrowth in the bowel (dysbiosis) may be an etiological factor in IBS. This has lead to studies in which the antibiotic agent rifaximin has been used to reduce the microbial burden in the bowel, to some extent alleviating the symptoms of IBS. Rifaximin is a member of the rifamycin class of antibiotics, which when administered orally has the distinctions of being gut specific coupled with poor systemic absorption, characteristics that are suggested to limit the development of bacterial resistance. The rifamycins are currently used to treat serious human diseases including tuberculosis, meningococcal disease, methicillin-resistant Staphylococcus aureus and Clostridium difficile infections. The use of rifamycins in the treatment of these diseases is associated with the development of antibiotic resistance over time. When considering the importance of the rifamycins in the treatment of serious human diseases, the large number of patients affected by IBS, and the lack of scientific evidence available on the development of antibiotic resistance to rifaximin over the long-term when used in the gut, it is advisable that the use of rifaximin as a therapy for IBS should be limited to single, acute, short-term treatment.