Human papillomaviruses (HPVs) are a family of double strand DNA viruses comprising more than 150 types. Selective infection of cutaneous or mucosal epithelia is a classic feature of HPV and their replication is closely linked to the differentiation and malignant transformation of the epithelium. HPV-16 and HPV-18 account for the majority of cancers of the cervix, anus, vagina, vulva, penis, tongue, thorax and tonsil. Adoptive immunotherapy with transgenic T cell receptor (TCR) T cells has emerged as a potential therapeutic strategy for human cancers. However, clinical translation of this therapy has achieved limited success in HPV-associated recurrent or metastatic disease while targeting HPV16-E6 or E7 antigens. Proteome-wide analysis of HPV-specific T cell responses in HPV-positive oropharyngeal cancer (OPC) patients revealed that T cell responses from these patients were not constrained to the E6 and E7 antigens; they also recognized E1, E2, E4, E5, and L1 proteins as dominant targets. These observations provided a ground-breaking insight into future development of cellular immunotherapies for HPV-associated cancers. We have now isolated multiple HLA class I and class II-restricted HPV-specific TCRs specific for E2, E5, E6 and E7 antigens and expressed multiple TCRs in Jurkat cells and human peripheral blood mononuclear cells. We have validated these TCRs using both in vitro and in vivo functional assays. Human T cells transduced with HPV-specific TCRs efficiently recognize HPV epitope sensitized target cells while the HPV-positive tumour cell recognition correlated with the expression of HPV-encoded antigens. Furthermore, adoptive transfer of HPV-specific TCR transduced T cells also blocked the outgrowth of HPV-positive tumours in NOD-Rag1null IL2rgnull (NRG) mice. More importantly, TCR-transduced T cells were detected in peripheral blood and HPV-positive tumours in NRG mice following adoptive immunotherapy.