Lung cancer continues to be the most common neoplasia and represents the leading cause of cancer-related death in the world. Nonetheless, contrary to expected projections, the decrease in incidence expected by decrease in tobacco exposure has been partially halted due to an increasing amount of lung cancer cases in nonsmokers, particularly in female patients. This led to the development of new hypotheses in terms of lung cancer etiology, including the involvement of oncogenic viruses such as the human papillomavirus (HPV). HPV role in the pathophysiology of lung cancer, including adenocarcinoma and squamous cell carcinoma, is currently under research. Exposure to HPV, and the resulting infection, can occur in several possible ways, including sexual transmission and airborne fomites. Main pathogenic occurrences include alterations in inhibition of p53 and retinoblastoma. This chapter presents the current evidence as to the role of HPV in the development of lung cancer, methods to establish HPV infection, and also explores the role of predisposing factors, as well as immunological and inflammatory factors in nonsmokers. Additionally, the role of other molecular factors, such as EGFR, interleukins 6 and 10, and others, is discussed. Finally, future perspectives in this new paradigm of lung cancer in nonsmokers are broadly reviewed.