The balance between tumor cell proliferation and apoptosis is a critical determinant of malignant tumor outgrowth. In a transgenic mouse model of beta cell tumorigenesis (Rip1Tag2), insulin-like growth factor II (IGF-II) is up-regulated during the onset of tumor cell proliferation. Disruption of IGF-II expression in these transgenic mice causes a dramatic increase of beta tumor cell (betaTC) apoptosis, indicating that IGF-II acts as a survival factor. Here we report that beta tumor cell lines derived from IGF-II-deficient Rip1Tag2 mice show a higher incidence of apoptosis than their wild-type counterparts. In particular, IGF-II-deficient betaTCs are more sensitive to apoptotic stimuli, such as serum deprivation and staurosporine, and to chemotherapeutic agents, such as daunomycin, etoposide, or vincristine. Thus, the lack of the survival factor IGF-II potentiates chemotherapeutic treatment of betaTCs. Furthermore, normal betaTCs can be sensitized to chemotherapy when transfected with a dominant-negative mutant of the IGF-I receptor. These results demonstrate a pivotal role for IGF-mediated signaling in the survival of tumor cells and, thus, raise the possibility of novel approaches toward cancer therapy by interfering with survival factor function.