Transgenic mice expressing the simian virus-40 large T-antigen (Tag) under the control of the insulin gene regulatory region offer a useful model for tumorigenesis. All the islets of Langerhans express Tag, although there is at first no aberrant proliferation. Over half of the islets become hyperplastic, however, and neovascularization of a further subset (about 10%)3 leads eventually to formation of highly vascularized solid tumours in 1-2% of islets by about 14 weeks of age. Here we show that the initial proliferative switch is correlated with focal activation of insulin-like growth factor II (IGF-II). Transfection with an antisense oligonucleotide to the IGF-II messenger RNA interferes with tumour cell proliferation in vitro, and transgenic mice homozygous for a disruption of the IGF-II gene develop tumours with reduced malignancy and a higher incidence of apoptosis. Several signals, in this case including an oncoprotein and a growth/survival factor, thus appear to be needed to elicit hyperproliferation.