Lung squamous cell carcinoma (SqCC) accounts for 30% of lung cancers, with over 400,000 deaths per year worldwide. Although evidence suggests that chronic lung injury drives carcinogenesis, a comprehensive understanding of this process remains elusive. Here, I used a comparative microarray analysis to identify gene expression differences shared between airway injury and squamous lung cancer. Of the 667 genes that exhibited differential expression following murine polidocanol and SO2 injury, 40.6% were additionally dysregulated in human SqCC. Among these, 150 genes were consistently upregulated and 54 downregulated relative to all controls. Examples included genes associated with increased cell cycling, aberrant cytokinesis and DNA repair, and enhanced tumour cell invasion and metastases. For 88.2% of identified genes, altered expression was associated with increased SqCC progression and patient mortality. These results establish a novel gene expression signature linking airway injury and lung cancer pathogenesis.