At least half of the patients with advanced-stage head and neck squamous cell carcinoma (HNSCC) develop recurrent or metastatic disease within the first two years after treatment. This thesis addresses clinical challenges regarding the management of advanced-stage HNSCC patients, including treatment toxicity, the need for novel treatment strategies and difficulties in detecting residual lymph node metastasis with current imaging modalities and intra-operatively. We describe a comparative study between two standard of care treatment regimes, prioritize potential targets for the use of antibody-drug-conjugates as novel treatment options for HNSCC and explore genes associated with replication stress in HNSCC, since exploitation of replication stress could be another innovative anti-cancer treatment strategy. Because salvage surgery often remains the patient’s last resort for curation in case of residual disease, early detection is pivotal. Assessing response to treatment however remains challenging. Other studies in this thesis therefore focus on identifying independent predictors for residual lymph node disease, evaluation the diagnostic performance of F-FDG-PET/CT for identification of residual disease and the search for novel imaging targets to improve identification of residual disease.