Introduction: Infections with the human papillomavirus, particularly types 16 and 18 (HPV16/18), are the major cause of numerous malignancies including cervical, anal, vulval, and head and neck cancers. Although the introduction of the HPV cancer vaccine (Gardasil™ and Cervarix™) is predicted to significantly reduce the incidence of cervical cancer, modelling has shown it will take 100 years to get over 90% reduction in cervical cancer. Importantly, these vaccines are not effective against a malignancy that has already developed. Therefore, there is a pressing need for effective treatments for this disease. Here we aim to develop drug targeted approach that selectively destroys cervical cancer cells and leave normal cells intact. Methods: Using large scale RNAi screening several genes were identified to selectively exert lethal effect on HPV-driven cancers while leaving non-HPV cells unaffected. One of these novel protein targets was the mitotic regulatory Aurora A kinase, which was previously reported to be over-expressed in numerous malignancies. Here we show the mechanism by which this occurs using a specific Aurora A inhibitor, MLN8237 (Alisertib). Results: We found that Alisertib was significantly more potent towards the HPV transformed cells, and selectively promoted apoptosis in the HPV cancers. The drug was shown to target the HPVE7 oncogene, and the apoptosis was sensitive to Mcl-1 but not Bcl-2 over-expression. Xenograft experiments with cervical cancer cell lines resulted in complete tumour loss from Alisertib treatment with mice tumour-free after 60 days while non-HPV cancer growth was merely delayed. Conclusion: These findings provide strong evidence that Alisertib represent a potent and highly targeted therapeutic against HPV-transformed cancers.