Despite its prevalence, the molecular basis of head and neck squamous cell carcinoma (HNSCC) remains poorly understood. Consequently, treatment alternatives for this disease are limited, and the prognosis remains extremely poor. We have identified the developmental transcription factor Grhl3 as a potent tumor suppressor of HNSCC in mice. Deletion of Grhl3 in adult oral epithelium results in both spontaneous tumours, and accelerated HNSCC development in the setting of exposure to oral carcinogens. Grhl3 loss evokes loss of expression of the protein kinase GSK-3b, a direct GRHL3 target, resulting in stabilisation of the proto-oncogene, c-Myc. Restoration of GSK-3b expression in HNSCC cell lines lacking both Grhl3 and GSK-3b results in reduced cell proliferation. Analysis of primary human HNSCC identifies a distinct subset that exhibit the Grhl3/GSK-3b/c-Myc signature potentially paving the way for more targeted therapies in cohorts of patients with this molecular lesion.