Human papillomaviruses (HPVs) are small, non-enveloped viruses with 55-nm-diameter icosahedral capsids containing double-stranded DNA genomes of approximately 8,000 bp. They infect squamous epithelia and cause warts. The transmission of warts was first demonstrated in the 19th century through experimental infections. Genital warts and cervical cancer were long thought to be venereal diseases, but experiments showed that they are caused by transmissible agents. Studies by Shope, Rous, and others demonstrated that some warts have a propensity for malignant progression, and that papillomaviruses are species-specific. Harald zur Hausen was the first to demonstrate that genital warts contain HPV genomes. Subsequent studies found related HPV sequences in cervical cancer tissues. Approximately 200 HPVs have been characterized, with some being high-risk and associated with malignancies. High-risk HPVs, such as HPV-16, are linked to cervical cancer, while low-risk HPVs cause benign warts. HPV-5 and HPV-8 are associated with epidermodysplasia verruciformis, a rare skin condition that can lead to skin cancers. HPV genomes are divided into early (E) and late (L) regions, with the E region encoding nonstructural proteins and the L region encoding capsid proteins. The life cycle of papillomaviruses is tightly linked to epithelial differentiation. The E1 and E2 proteins are crucial for viral genome replication. The E2 protein interacts with the viral DNA helicase E1 and is involved in viral genome segregation during cell division. Integration of the HPV genome into a host chromosome leads to the expression of E6 and E7 genes, while other viral DNA is deleted or not expressed. Loss of E2 repressor function may result in deregulated E6 and E7 expression. HPV E6 and E7 oncoproteins inactivate tumor suppressors p53 and pRB, contributing to malignant progression. HPV E7 proteins destabilize pocket proteins, leading to cell cycle deregulation. HPV E6 proteins inactivate p53, eliminating the trophic sentinel response triggered by E7. HPV E6 and E7 oncoproteins also induce telomerase activity, which is critical for cellular immortalization. These proteins contribute to genomic instability by inducing centrosome abnormalities and aneuploidy. High-risk HPV E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability. The continued expression of E6 and E7 in cervical cancers is necessary for the maintenance of the transformed phenotype. The transforming activities of high-risk HPVs are driven by their ability to replicate in growth-arrested epithelial cells and establish long-term persistence. High-risk HPVs differ from low-risk HPVs in their ability to induce genomic instability and malignantHuman papillomaviruses (HPVs) are small, non-enveloped viruses with 55-nm-diameter icosahedral capsids containing double-stranded DNA genomes of approximately 8,000 bp. They infect squamous epithelia and cause warts. The transmission of warts was first demonstrated in the 19th century through experimental infections. Genital warts and cervical cancer were long thought to be venereal diseases, but experiments showed that they are caused by transmissible agents. Studies by Shope, Rous, and others demonstrated that some warts have a propensity for malignant progression, and that papillomaviruses are species-specific. Harald zur Hausen was the first to demonstrate that genital warts contain HPV genomes. Subsequent studies found related HPV sequences in cervical cancer tissues. Approximately 200 HPVs have been characterized, with some being high-risk and associated with malignancies. High-risk HPVs, such as HPV-16, are linked to cervical cancer, while low-risk HPVs cause benign warts. HPV-5 and HPV-8 are associated with epidermodysplasia verruciformis, a rare skin condition that can lead to skin cancers. HPV genomes are divided into early (E) and late (L) regions, with the E region encoding nonstructural proteins and the L region encoding capsid proteins. The life cycle of papillomaviruses is tightly linked to epithelial differentiation. The E1 and E2 proteins are crucial for viral genome replication. The E2 protein interacts with the viral DNA helicase E1 and is involved in viral genome segregation during cell division. Integration of the HPV genome into a host chromosome leads to the expression of E6 and E7 genes, while other viral DNA is deleted or not expressed. Loss of E2 repressor function may result in deregulated E6 and E7 expression. HPV E6 and E7 oncoproteins inactivate tumor suppressors p53 and pRB, contributing to malignant progression. HPV E7 proteins destabilize pocket proteins, leading to cell cycle deregulation. HPV E6 proteins inactivate p53, eliminating the trophic sentinel response triggered by E7. HPV E6 and E7 oncoproteins also induce telomerase activity, which is critical for cellular immortalization. These proteins contribute to genomic instability by inducing centrosome abnormalities and aneuploidy. High-risk HPV E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability. The continued expression of E6 and E7 in cervical cancers is necessary for the maintenance of the transformed phenotype. The transforming activities of high-risk HPVs are driven by their ability to replicate in growth-arrested epithelial cells and establish long-term persistence. High-risk HPVs differ from low-risk HPVs in their ability to induce genomic instability and malignant