Head and neck cancer is the seventh most common cancer worldwide, and despite aggressive radiotherapy and chemotherapy treatment regimens the 5 year overall survival rate resides at 40-50%. Approximately 60% of patients develop progressive disease despite radical surgery, radiotherapy and chemotherapy with cisplatin/carboplatin and 5-fluorouracil combinations. Immunotherapy using PD-L1 checkpoint inhibitors has recently been approved but responses are only seen in 25-29% of patients, hence the median survival for patients with recurrent or metastatic disease remains a mere ~ 10 months. High mutation rates predispose head and neck cancers to the development of drug resistance, rapidly rendering therapies ineffective. Additionally, the diversity of anatomical location, epidemiological factors, treatment toxicity, and incomplete knowledge of the genomic aberrations that drive carcinogenesis necessitate the need to identify better potential therapeutic strategies. Here, we have produced a cohort of primary xenografts and cell lines generated from resected head and neck cancer biopsy specimens, which histologically recapitulate the human disease. These xenografts and cell lines retain the genomic signature of human disease, are generated from individual patients, and are renewable, hence multiple treatments can be simultaneously examined, providing the opportunity to test proposed personalised medicine strategies, and facilitate novel therapeutic development linked with companion biomarker discovery. We provide a rapid pipeline for phenotypically guiding individual patient treatment based on in vitro and in vivo response data in these patient generated models, using both novel and existing therapeutics that are either rescued, repurposed, in development, or are known to be effective in an undefined subgroup of patients. The potential impact of this pipeline has already driven one patient into disease remission with the ultimate aim to expand targeted therapeutic avenues and improve overall patient outcomes.