In multiple anatomic sites, patients with cancers associated with the Human Papillomavirus (HPV) experience better locoregional control and overall survival after radiotherapy and/or chemoradiotherapy than patients with HPV-negative cancers. These improved outcomes suggest that relatively unique biological features in HPV-positive cancers may increase sensitivity to DNA damaging agents as well as an impaired DNA damage response. This review will address potential biological mechanisms driving this increased sensitivity of HPV-positive cancer to radiation and/or chemotherapy. This review will discuss the clinical and preclinical observations that support the intrinsic radiosensitivity and/or chemosensitivity of HPV-positive cancers. Furthermore, this review will highlight the molecular mechanisms for increased radiation sensitivity using the classical "4 Rs" of radiobiology: repair, reassortment, repopulation, and reoxygenation. First, HPV-positive cancers have increased DNA damage due to increased oxidative stress and impaired DNA damage repair due to the altered activity TP53, p16, TIP60, and other repair proteins. Second, irradiated HPV-positive cancer cells display increased G2/M arrest leading to reassortment of cancer cells in more radiosensitive phases of the cell cycle. In addition, HPV-positive cancers have less radioresistant cancer stem cell subpopulations that may limit their repopulation during radiotherapy. Finally, HPV-positive cancers may also have less hypoxic tumor microenvironments that make these cancers more sensitive to radiation than HPV-negative cells. We will also discuss extrinsic immune and microenvironmental factors enriched in HPV-positive cancers that facilities responses to radiation. Therefore, these potential biological mechanisms may underpin the improved clinical outcomes often observed in these virally induced cancers.