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Myt3is a prosurvival factor in pancreatic islets; however, its role in islet-cell development is not known. Here, we demonstrate that myelin transcription factor 3 (Myt3) is expressed in migrating islet cells in the developing and neonatal pancreas and thus sought to determine whether Myt3plays a role in this process. Using an ex vivo model of islet-cell migration, we demonstrate that Myt3suppression significantly inhibits laminin-V/integrin-β1-dependent α- and β-cell migration onto 804G, and impaired 804G-induced F-actin and E-cadherin redistribution. Exposure of islets to proinflammatory cytokines, which suppress Myt3expression, had a similar effect, whereas Myt3overexpression partially rescued the migratory ability of the islet cells. We show that loss of islet-cell migration, due to Myt3suppression or cytokine exposure, is independent of effects on islet-cell survival or proliferation. Myt3suppression also had no effect on glucose-induced calcium influx, F-actin remodeling or insulin secretion by β-cells. RNA-sequencing (RNA-seq) analysis of transduced islets showed that Myt3suppression results in the up-regulation of Tgfbi, a secreted diabetogenic factor thought to impair cellular adhesion. Exposure of islets to exogenous transforming growth factor β-induced (Tgfbi) impaired islet-cell migration similar to Myt3suppression. Taken together, these data suggest a model by which cytokine-induced Myt3suppression leads to Tgfbide-repression and subsequently to impaired islet-cell migration, revealing a novel role for Myt3in regulating islet-cell migration.