The factors that normally regulate the proliferation of the insulin-producing pancreatic beta-cell largely remain elusive although several factors have been identified that influence beta-cell growth in vitro. The adult beta-cell is normally virtually quiescent, but its replicatory activity can be enhanced in vitro by certain nutrients and growth factors, and long-term alterations in beta-cell mass constitute an important means to accommodate an increased demand for insulin. Likewise, expansion of the beta-cell mass by recruitment of beta-cells to proliferate may constitute a means by which the organism can compensate for the loss or dysfunction of beta-cells occurring in diabetes. However, neither in human or animal models for type-1 diabetes, nor in type-2 diabetes, is beta-cell regeneration a noteworthy feature. Thus, if beta-cells could be induced to replicate at a higher rate, this may prove beneficial in maintaining normoglycaemia, since the beta-cell mass is a major determinant of the total amount of insulin that can be secreted by the pancreas. The present review will focus on the normal regulation of beta-cell mitogenesis and hormones production in vitro and in vivo, and furthermore, will present evidence for an insufficient extent of beta-cell regeneration in different forms of diabetes mellitus. Additionally, the possibility of manipulating beta-cell proliferation by peptides and genetic engineering, and the significance of beta-cell mitogenesis in islet transplantation will be discussed in relation to treatments of diabetes mellitus.