Xenotoxic damage in inflammatory diseases, including inflammatory bowel disease (IBD), is importantly compounded by reduced activity of the xenobiotic transporter ABCG2 during the inflammatory state. An association between activation of the unfolded protein response pathway and inflammation prompted us to investigate the possibility that reduced ABCG2 activity is causally linked to this response. To this end we correlated expression of ABCG2 and the unfolded protein response marker GRP78 in colon biopsies from healthy individuals (n=9), and patients with inactive (n=67), or active (n=55) IBD, ischemic colitis (n=10), or infectious colitis (n=14). In addition, tissue-specimens throughout the small bowel from healthy individuals (n=27), and from patients with inactive (n=9) or active (n=25) Crohn's disease were co-stained for ABCG2 and GRP78. In all biopsies from patients with active inflammation, irrespective of the underlying disease, an absolute negative correlation is observed between epithelial ABCG2 expression and GRP78 expression, suggesting that inflammation-dependent activation of the unfolded protein response is responsible for suppression of ABCG2 function. The link between the unfolded protein response and functional ABCG2 expression is further corroborated by live-imaging of ABCG2 expressing cells which show that various inflammatory mediators, including nitric oxide, activate the unfolded protein response and concomitantly reduce plasma membrane localisation as well as transport function of ABCG2. Thus a novel mechanism for explaining xenobiotic stress during inflammation emerges, in which intestinal inflammation actives the unfolded protein response in turn abrogating defences against xenobiotic challenge by impairing ABCG2 expression and function.