Human papillomavirus (HPV) E6 and E7 viral oncoproteins play the pivotal role in driving the cells toward oncogenesis. In their process of replicating the viral genome, they can induce all the hallmarks of a cancer cell, i.e., uncontrolled cellular proliferation, angiogenesis, invasion, metastasis, and unrestricted telomerase activity along with the evasion of apoptosis and growth suppressors’ activity. E6 associates with host UBE3A/E6-AP ubiquitin-protein ligase, and inactivates tumor suppressors TP53 and TP73 by targeting them to the 26S proteasome for degradation. The complex E6/E6AP targets several other substrates to degradation via the proteasome including host DLG1 or NFX1, a repressor of human telomerase reverse transcriptase (hTERT). The resulting increased expression of hTERT prevents the shortening of telomere length leading to cell immortalization. Other cellular targets including BAK1, Fas-associated death domain-containing protein (FADD) and procaspase 8, are degraded by E6/E6AP causing inhibition of apoptosis. E6 also inhibits immune response by interacting with host IRF3 and TYK2. These interactions prevent IRF3 transcriptional activities and inhibit TYK2-mediated JAK-STAT activation by interferon alpha resulting in inhibition of the interferon signaling pathway.