A large number of clinical studies using breath testing and a smaller number of studies using quantitative cultures of the upper small intestine established a link between irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). A series of 12 studies both prospective and retrospective in design in a population of patients with SIBO without IBS showed that the non-absorbable antibiotic rifaximin can eradicate SIBO as proved through decrease of the exhaled hydrogen and methane in breath tests. The efficacy of rifaximin was superior over the comparator treatment in most of these studies. Based on these findings, short course rifaximin was tested in various concentrations in eight open-label trials in patients with IBS and proven SIBO by breath test. Similar efficacy of rifaximin was shown in SIBO eradication; this was accompanied by improvement of the global score for IBS symptoms. Finally, five double-blind randomized clinical trials were conducted in patients with IBS; four were placebo-controlled. The larger trials were TARGET 1 and TARGET 2 studies testing rifaximin at a regimen of 550 mg tid for 14 days. All trials showed a significant superiority of rifaximin over comparator for the improvement of global symptoms of IBS and bloating. Although the aforementioned results render rifaximin a revolutionary therapeutic approach for IBS, several concerns on induction of antimicrobial resistant flora remain.