Rationale: Despite intense research efforts, the etiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Objective: To discover novel genes and/or cellular pathways involved in the pathogenesis of the disease. Methods/Measurements: Expression profiling of disease progression in an animal model of the disease was compared with all publicly available expression profiles both from human patients and animal models. Hypoxia inducible factor 1a expression was determined in tissue microarrays containing tissue samples of human patients, followed by computerized image analysis. Main results: A highly statistically significant, prioritized list of differentially expressed genes in idiopathic and/or modeled pulmonary fibrosis. Extending beyond target identification, a series of data meta- analyses produced a number of biological hypotheses on disease pathogenesis. From these, the role of hypoxia inducible factor 1a was further explored to reveal overexpression in the hyperplastic epithelium of fibrotic lungs, colocalized with its target genes p53 and VEGF. Conclusions Comparative expression profiling was shown to be a highly efficient method in identifying deregulated genes and pathways. Moreover, tissue microarrays and computerized image analysis allowed for the high throughput and unbiased assessment of histopathological sections, adding substantial confidence to pathological evaluations. More importantly, our results suggest an early primary role of hypoxia inducible factor 1 in alveolar epithelial cell homeostasis and disease pathogenesis, provide insights on the pathophysiological differences of different interstitial pneumonias, and indicate the importance of assessing the efficacy of pharmacological inhibitors of HIF-1 activity in the treatment of pulmonary fibrosis.