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Pancreatic -cell loss and dysfunction are critical components of all types of diabetes. Human and rodent -cells are able to proliferate, and this proliferation is an important defense against the evolution and progression of diabetes. Transforming growth factor- (TGF-) signaling has been shown to affect -cell development, proliferation, and function, but -cell proliferation is thought to be the only source of new -cells in the adult. Recently, -cell dedifferentiation has been shown to be an important contributory mechanism to -cell failure. In this study, we tie together these two pathways by showing that a network of intracellular TGF- regulators, smads 7, 2, and 3, control -cell proliferation after -cell loss, and specifically, smad7 is necessary for that -cell proliferation. Importantly, this smad7-mediated proliferation appears to entail passing through a transient, nonpathologic dedifferentiation of -cells to a pancreatic polypeptide-fold hormone-positive state. TGF- receptor II appears to be a receptor important for controlling the status of the smad network in -cells. These studies should help our understanding of properly regulated -cell replication.