Laryngeal squamous cell carcinoma is a frequent and significant cause of morbidity and mortality. Here we explore the biological basis of this aggressive tumour, and identify two cell-cell adhesion genes as recurrently mutated in this malignancy. We first perform exome sequencing of four laryngeal carcinomas and their matched normal tissues. Among the 569 genes found to present somatic mutations, and based on their recurrence or functional relevance in cancer, we select 40 for further validation in 86 additional laryngeal carcinomas. We detect frequent mutations (14 of 90, 15%) in CTNNA2 and CTNNA3-encoding α-catenins. Functional studies reveal an increase in the migration and invasive ability of head and neck squamous cell carcinoma cells producing mutated forms of CTNNA2 and CTNNA3 or in cells where both α-catenins are silenced. Analysis of the clinical relevance of these mutations demonstrates that they are associated with poor prognosis. We conclude that CTNNA2 and CTNNA3 are tumour suppressor genes frequently mutated in laryngeal carcinomas.