Though vaccine uptake and public support have risen since the release of the first HPV vaccines, the United States has far lower initiation and completion rates for the HPV vaccine series in comparison to other vaccines indicated for youth. Disparities are even greater in the Appalachian regions. Understanding factors contributing to these discrepancies is vital to improving vaccine rates in Appalachia. A comprehensive literature search identified all articles pertaining to HPV vaccination in children and adolescents living in Appalachia. The final 15 articles were included in a systematic review of the topic.