Infection by high-risk human papillomaviruses (HPV) and persistent expression of the viral oncogenes E6 and E7 are causally linked to the development of cervical cancers. These oncogenes require additional events for the complete transformation of human epithelial cells. Although exaggerated levels of c-Myc are observed in many cases of cervical cancer, the actual function of c-Myc in the process of HPV-mediated transformation is unclear. Here, we show that analogous to activated alleles of Notch1, c-Myc can cooperate with E6/E7 in epithelial transformation and can substitute for CBF1-dependent signals generated by Notch1. In addition, dominant-negative forms of c-Myc block transformation by activated Notch1, E6 and E7, suggesting that c-Myc is required for HPV16-mediated transformation.