Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous group of tumors that develop via one of the two primary carcinogenic pathways: chemical carcinogenesis through exposure to tobacco and alcohol or virally induced tumorigenesis. HPV-negative (HPV-) and HPV-positive (HPV+) HNSCCs represent distinct disease entities, and the latter is associated with a substantially improved outcome. Differences in molecular pathogenesis account for these different outcomes; their staging classification and therapeutic regimens also are currently being re-evaluated, and re-evaluation would be significantly facilitated by robust biomarkers for patient stratification. Through the past years, with the advent of the omics era, a better understanding of the biology of HNSCC has been accompanied by the exploration of a large and rapidly expanding number of targeted agents, which might be incorporated into standard management in the future. In the era of personalized medicine, and with a view to improve the outcomes and quality of life of patients, current research efforts also are focused on the identification of specific biomarkers for treatment selection. Treatment of HNSCC is expected to change in the next decade if molecular biology continues to evolve. Herein, we highlight research progress in HNSCC presented at the fifth International Conference on Innovative Approaches in Head and Neck Oncology (ICHNO).