Abstract: Biomarkers of lung disease are provided. The biomarkers comprise target genomic DNA sequences having one or more CpG dinucleotides that are differentially methylated in genomic DNA of subjects having lung disease as compared to normal subjects or subjects not having lung disease. In one exemplary embodiment, methylation status profiles of 71 CpG sites mapping to 67 unique genes are significantly associated with at least one of three lung function decline measures associated with lung disease. Other biomarkers significantly associated with cigarette smoking-related lung function decline, with age-related lung function decline, and with the intensifying effects of cigarette smoking on lung function decline with age are also provided.