Mucosal surfaces and the epithelial cells that line them are constantly exposed to potential pathogens. The evidence reviewed above suggests that the innate immune system, comprised of TLRs and their associated molecules, plays a pivotal role in the regulation of mucosal inflammation in response to invading pathogens. However, the very fact that these mucosal surfaces are bathed in potential pathogens as part of their daily existence and yet don't develop inflammation under normal conditions raises an important scientific ques-tion: When does epithelial TLR signaling within mucosal surfaces become pathological? Or stated differently, when is the balance tipped between "physiological" signaling and "pathological" signaling in favor of a pathological response? A definitive answer to this important question not only is necessary to fully elucidate the steps required for the development of mucosal inflammatory diseases, but is central for the design of effective anti-inflammatory strategies.