The insulin-like growth factor II is mitogenic for a number of cell types and can inhibit apoptosis. The frequent expression of this gene in human and experimental animal tumors indicates that insulin-like growth factor-2 may play an important role in tumor development. It has also been hypothesized that overexpression of this growth factor may be responsible for the increased incidence of childhood tumors in patients with Beckwith-Wiedemann syndrome. To assess the effects of Igf2 on tumor development we produced six transgenic mouse lines that express the gene under the control of the H19 enhancers. Transgenic expression was initiated in the embryonic period but remained high in several adult tissues, including the mammary gland, lung, and liver. Adult transgenic females from five of the transgenic lines developed often multiple mammary tumors that had the ability to metastasize. Increased incidence of other solid tumors was also noted in older mice. These findings indicate that Igf2 expression increases the probability of malignant transformation and that the mammary gland is at a particularly high risk of tumor development in response to chronic increase in Igf2 gene dosage.