The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer is rising in the Western world, but little is known about transmission of the infection and the premalignant phase of the disease. In this article there is an overview of current knowledge with focus on transmission of HPV and risk factors which may lead to persistent infection and eventually cancer. Furthermore, there is a discussion about issues concerning the ability to measure and detect infection and the premalignant stadium in the oropharyngeal tissue.