This review will focus on the emerging role of the insulin receptor (IR) in cancer. Several epidemiological studies have shown that insulin resistance states, characterized by hyperinsulinemia, are associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon and kidney. Recent data have elucidated some molecular mechanisms by which IR is involved in cancer. First, IR is overexpressed in several human malignancies. Interestingly, one of the two IR isoform (IR-A) is especially overexpressed in cancer. IR-A is the IR fetal isoform and has the peculiar characteristic to bind not only insulin but also IGF-II. Second, IR forms hybrid receptors with the homologous IGF-IR, which is also commonly overexpressed in cancer. These hybrid receptors containing IR-A hemidimers have broad binding specificity as they bind IGF-I and also IGF-II and insulin. By binding to hybrid receptors, insulin may stimulate specific IGF-IR signaling pathways. Overexpression of IR-A is, therefore, a major mechanism of IGF system overactivation in cancer. These findings may have important implications for both the prevention and treatment of common human malignancies. They underline the concept that hyperinsulinemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmachological approaches to avoid an increased risk for cancer. IR-A isoform and hybrid receptors should be regarded, therefore, as potential molecular targets for novel anti-cancer therapies.