There is currently much interest in the possibility to treat chronic diseases by cell replacement or regenerative therapies. Most of these studies focus on the manipulation of undifferentiated stem cells. However, tissue repair and regeneration can also be achieved by differentiated cells, which, in certain conditions, can even transdifferentiate to other cell types. Such transdifferentiations can lead to tissue metaplasia. The pancreas is an organ wherein metaplasia has been well investigated and for which experimental models have been recently developed allowing to unravel the molecular basis of transdifferentiation. Pancreatic metaplasias studied so far include the conversion of exocrine acinar cells to duct cells, exocrine cells to endocrine islet cells, endocrine cells to duct cells, and acinar cells to hepatocytes. Epitheliomesenchymal transitions have also been described. The available evidence indicates that mature cells can be reprogrammed by specific environmental cues inducing the expression of cell type-specific transcription factors. For example, the glucocorticoid hormone dexamethasone induces pancreatic transdifferentiation to hepatocytes, whereas the combination of epidermal growth factor and leukemia-inhibitory factor induces exocrine-endocrine transdifferentiation in vitro. Further unravelling of the involved signal transduction pathways, transcription factor networks, and chromatin modifications is required to manipulate metaplasia at will and to apply it in tissue repair or regeneration.