Head and neck squamous cell carcinoma (HNSCC) represents the 5th most common cancer in the world, characterized by poor prognosis. Significant recent therapeutic advances changed the HNSCC brand but superior survival is limited to a small percentage of patients. Promoting novel treatment strategies such as targeted drug therapy or immunotherapy in the management of earlier stages of HNSCC, as well as achieving a better patients’ selection might increase treatment yield. Such goals can be explored by employing a window of opportunity clinical trial design. Window trials involve the administration of a novel drug between cancer diagnosis and scheduled definitive surgical treatment. Tumor tissue biopsies are obtained at diagnosis and after the investigation treatment, at time of surgery. Additional biospecimens, such as blood, and radiographic exams are collected along. Such study design allows for measurement of direct tumor response to novel agents in treatment- naïve patients. It also enables the evaluation of the safety profile of the drug in early treatment setting as well as collection and analysis of biomarkers that could potentially predict sensitivity or resistance to the investigated drug. We present here two window of opportunity clinical protocols that we conducted in patients with newly diagnosed HNSCC. One clinical trial involves a biologic targeted drug and the other an immunotherapeutic. EGFR inhibitors are the only targeted drugs that so far showed significant clinical efficacy in HNSCC. The monoclonal antibody cetuximab is now widely utilized as a single agent, in combination with chemotherapy or as a radiosensitizer. The EGFR tyrosine kinase inhibitor Erlotinib was tested in metastatic and recurrent HNSCC and it was dismissed from further evaluations because of a limited response rate of 4%. Our window of opportunity clinical trial exploring the administration of Erlotinib in neoadjuvant setting, before definitive surgery, shows significant activity of Erlotinib when given in a dose adjusted per smoking status. We also show that early PET scans can predict tumor response. The immunotherapeutic checkpoint inhibitors are approved for use as single agents or in combination with chemotherapy in metastatic or recurrent HNSCC. Although there are exceptional responders and patients with significant prolongation of survival, the response rate remains below 20% for single agent utilization. We and others are conducting window of opportunity clinical protocols with checkpoint inhibitors searching for biologic markers to correlate with therapeutic response. In addition, our ongoing protocol aims to identify potential difference in tumor response to immunotherapy between HPV positive and HPV negative patients. It is postulated that such protocols will help with better patients’ selection for future clinical trials with the goal to improve treatment results. Advantages and hurdles in designing and conducting window of opportunity clinical protocols in patients with HNSCC will be discussed.