The development of intestinal-type gastric cancer is preceded by loss of parietal cells (oxyntic atrophy) and the induction of metaplastic cell lineages in the gastric mucosa. For example, mouse models have shown that spasmolytic polypeptide-expressing metaplasia can develop following oxyntic atrophy through transdifferentiation of zymogen-secreting chief cells. Evolution of spasmolytic polypeptide-expressing metaplasia from chief cells occurs via a coordinated dismantling of their secretory apparatus and reprogramming of their transcriptome. Increasing evidence suggests that the process of chief cell reprogramming requires the influence of inflammatory cytokines and requires both zymogen granule autophagy and alterations in gene transcription. It is likely that spasmolytic polypeptide-expressing metaplasia is a physiological repair mechanism that is similar to those that occur in other tissues (eg, pancreas) for recruiting reparative progenitor cells in response to mucosal wounds. Chronic inflammation can induce a recurring pattern of persistent reprogramming/metaplasia that increases the risk for neoplasia.