During the last decade our understanding of the regulation of gastric acid secretion has changed considerably. The recognition that gastrin acts mainly by releasing histamine from the enterochromaffin‐like (ECL) cell is of major importance. It is now necessary to review and seek new explanations for the development of tolerance and for the post‐treatment acid hypersecretion that may be observed when treatment with acid‐secretory inhibitors is discontinued. Tolerance and rebound related to H2‐receptor antagonists has previously been explained as upregulation of gastrin and/or histamine H2‐receptors, and/or an increased parietal cell mass. Experimental evidence for these theories is scarce. On the other hand, tolerance can now be explained by a gastrin‐induced increase in ECL cell‐derived histamine at the parietal cell H2‐receptor competing with the antagonist. The lack of tolerance to proton pump inhibitors may be explained by their mode of action, being non‐competitive and acting at the H+, K+‐ATPase rather than at stimulatory receptors. Post‐treatment rebound acid hypersecretion can be understood as gastrin upregulating and/or stimulating growth of the ECL cell, leading to increased amounts of releasable histamine post‐treatment. Novel experimental data strongly support this view of the development of tolerance and post‐treatment rebound acid hypersecretion.