To regulate inappropriate or excessive acid secretion that may be harmful not only to surrounding mucosal cells but also parietal cells themselves, versatile mechanisms operate to control acid secretion. In this article elaborate mechanisms that participate in the control of acid secretion are described with our data and a review of relevant findings in the literature concerning the action or secretion of key regulatory molecules. The analysis of the regulatory mechanisms revealed that appropriate secretory control can be achieved by multiple feedback regulations, which are closely coordinated with mucosal defense. In the feedback circuits, the regulatory factors cannot be simply categorized into either aggressive or defensive factors. Therefore we propose that the mucosal integrity and tissue homeostasis would be better understood by a feedback loop model rather than by a dualistic balance model.