Human papillomavirus (HPV) is the most common sexually transmitted infectious agent worldwide, being also responsible for 5% of all human cancers. The integration and hypermethylation mechanisms of the HPV viral genome promote the unbalanced expression of the E6, E7 and E5 oncoproteins, which are crucial factors for the carcinogenic cascade in HPV-induced cancers. This review highlights the action of E6, E7 and E5 over key regulatory targets, promoting all known hallmarks of cancer. Both well-characterized and novel targets of these HPV oncoproteins are described, detailing their mechanisms of action. Finally, this review approaches the possibility of targeting E6, E7 and E5 for therapeutic applications in the context of cancer. •HPV is the main etiological factor of 5% of all human cancers.•E6, E7 and E5 oncoproteins are the main drivers of HPV carcinogenesis.•HPV oncoproteins are implicated in all hallmarks of cancer.•Targeting E6, E7 and E5 is a future promising goal for disease treatments.