The invention provides the identification of oncogenic pathways activated in cytologically normal airway cells of individuals having or at risk of having lung disease, as well as specific gene expression patterns (biomarkers) associated with pathway activation. These biomarkers and pathways may provide prognostic and/or diagnostic indicators in lung disease, e.g., lung cancer. Additionally, these pathways and biomarkers may provide therapeutic targets for the treatment of lung disease, as well as markers for the assessment of treatment efficacy.