This review discusses the role of human papillomavirus (HPV) in the development of head and neck squamous cell carcinomas (HNSCC), with a focus on viral integration and its impact on therapeutic outcomes. HPV is a double-stranded DNA virus that can integrate into the host genome, leading to episomal or integrated forms. Patients with HPV-positive HNSCC generally have a better prognosis, except for those with fully integrated HPV, who show worse clinical outcomes due to reduced viral gene expression and limited T cell infiltration. The current approach of testing for HPV positivity alone without considering integration status is insufficient for effective therapy. The review highlights the importance of HPV integration as a determinant of response to therapies and suggests novel therapeutic avenues to reduce cancer burden and improve survival. It also discusses the molecular mechanisms of HPV replication, the differences between HPV-negative and positive HNSCC in terms of immune characteristics, genetic alterations, and mutational patterns. The integration of HPV into the host genome is a dynamic process that can lead to genetic alterations, oncogene activation, and tumor suppressor inactivation. HPV integration is associated with increased genetic instability and altered host gene expression, contributing to the progression of HNSCC. The review also explores the signaling pathways involved in HPV integration, such as DNA damage response and the PI3K-AKT-mTOR pathway, and discusses future directions for targeting HPV integration to improve therapeutic outcomes. Overall, the review emphasizes the importance of understanding HPV integration in the context of HNSCC and its potential as a therapeutic target.This review discusses the role of human papillomavirus (HPV) in the development of head and neck squamous cell carcinomas (HNSCC), with a focus on viral integration and its impact on therapeutic outcomes. HPV is a double-stranded DNA virus that can integrate into the host genome, leading to episomal or integrated forms. Patients with HPV-positive HNSCC generally have a better prognosis, except for those with fully integrated HPV, who show worse clinical outcomes due to reduced viral gene expression and limited T cell infiltration. The current approach of testing for HPV positivity alone without considering integration status is insufficient for effective therapy. The review highlights the importance of HPV integration as a determinant of response to therapies and suggests novel therapeutic avenues to reduce cancer burden and improve survival. It also discusses the molecular mechanisms of HPV replication, the differences between HPV-negative and positive HNSCC in terms of immune characteristics, genetic alterations, and mutational patterns. The integration of HPV into the host genome is a dynamic process that can lead to genetic alterations, oncogene activation, and tumor suppressor inactivation. HPV integration is associated with increased genetic instability and altered host gene expression, contributing to the progression of HNSCC. The review also explores the signaling pathways involved in HPV integration, such as DNA damage response and the PI3K-AKT-mTOR pathway, and discusses future directions for targeting HPV integration to improve therapeutic outcomes. Overall, the review emphasizes the importance of understanding HPV integration in the context of HNSCC and its potential as a therapeutic target.