Asthma and chronic obstructive pulmonary disease (COPD) are difficult to treat due to heterogeneity in symptom presentation and the multiple cell types, molecular mechanisms, environmental exposures, and genetic factors at play. Though pharmacotherapeutics exist, these are not effective in all patient populations. Prenylation is a post-translational modification whereby a hydrophobic isoprenoid is irreversibly conjugated to a target protein. This modification is catalyzed by heterodimeric prenyltransferases, including FNT, GGT-1, GGT-2 and GGT-3. Protein prenylation determines the localization and signal transduction for over 300 proteins, including members of the Ras superfamily. There is limited information about the role of protein prenylation in asthma and COPD pathobiology. The overarching hypothesis of this thesis is that protein prenylation, through the mRNA expression, protein abundance, and activity of prenyltransferases, is altered by cigarette smoke exposure and inflammation, and regulates pathophysiological processes associated with chronic lung disease. Using unbiased proteomics, we identified pathways altered in a house dust mite-challenge mouse model of allergic asthma. Comparing the proteome in bronchial alveolar lavage fluid and lung tissue of house dust mite-exposed and allergen-naïve mice, we identified 2675 distinct proteins, with great diversity between lung tissue and BALF, in particular in allergen-exposed animals. Bioinformatic analysis identified tissue-BALF interactions, for example pathways involving B-cell signaling in allergic mice. This approach did not identify the protein prenylation pathway as being altered by allergen challenge, however this does not preclude changes in prenylation activity. We examined prenyltransferases in the context of COPD, first showing that mRNA and protein for FNT, GGT-1 and GGT-2 are present in epithelial, endothelial and mesenchymal cells of the human lung. Using human lung fibroblast cultures, we revealed that prenyltransferase activity and membrane anchoring of protein prenylation targets increases with exposure to cigarette smoke extract. Stimulating lung fibroblasts from COPD donors with TNF and/or IL-1β induced IL-8 and GM-CSF secretion, and was differentially blunted by different prenyltransferase inhibitors. In the course of this project, a new prenyltransferase (geranylgeranyltransferase-3, GGT-3) was identified from another group, thus we confirmed its expression in cultured human lung cells, and used in silico molecular docking to predict that several prenyltransferase inhibitors may also inhibit GGT-3. Therefore effects on GGT-3 may have contributed to the results from our screen of prenyltransferase inhibitors in lung fibroblasts. In summary, this thesis provides first time data that release of inflammatory mediators is partially regulated by prenyltransferases, and suggests a role for prenyltransferases in the pathophysiological mechanisms in inflammation associated with chronic lung disease.