Abstract Head and neck squamous cell carcinomas (HNSCC) are aggressive neoplasms that result in debilitating changes in speech, appearance, and quality of life in humans. Response rates in HNSCC patients have remained relatively unchanged over the years, especially in patients with human papillomavirus (HPV) negative HNSCC highlighting the critical need for novel strategies to meet the therapeutic needs of this patient population. As recognized by PAR-17-245, a critical step in discovering novel therapies for HNSCC patients is the development of tumor models that can reliably recapitulate human disease biology, heterogeneity and therapeutic response. The overall goal of this application is to validate and credential a panel of patient- derived and immunocompetent models of HNSCC. Systematic and in-depth comparison of histopathologic, genomic, and therapeutic response profiles will be performed across multiple preclinical platforms in vitro (organoids) and in vivo (allografts/xenografts). Paired in vitro and in vivo models across these platforms will be used to assess their response to standard of care chemoradiation and immune checkpoint blockade. The models will also be used to screen the activity of novel and FDA-approved agents (‘drug repurposing’) targeting critical pathways implicated in the pathogenesis of HNSCC. The application builds on an existing collaboration between several investigators at Roswell Park Comprehensive Cancer Center with extensive experience and expertise in mammalian models, head and neck cancer, cancer imaging, tumor immunology, genomics, bioinformatics and cancer therapeutics. The project will employ innovative multimodal functional imaging methods to better define and enhance the true translational utility of mammalian models. The proposal will establish a robust panel of credentialed mammalian models of HNSCC and enable development of an integrated preclinical pipeline to assess efficacy of novel therapeutics, identify resistance mechanisms and enable biomarker discovery in HNSCC.