Chronic obstructive pulmonary disease (COPD) is a progressive and devastating chronic lung condition that has a significant global burden, both medically and financially. Currently there are no medications that can alter the course of disease. At best, the drugs in clinical practice provide symptomatic relief to suffering patients by alleviating acute exacerbations. Most of current clinical research activities are in late severe disease with lesser attention given to early disease manifestations. There is as yet, a lack of understanding of the underlying mechanisms of disease progression and the molecular switches that are involved in their manifestation. Small airway fibrosis and obliteration are known to cause fixed airflow obstruction in COPD, and the consequential damage to the lung has an early onset. So far, there is little evidence of the mechanisms that underlie this aspect of pathology. However, emerging research confirms that airway epithelial reprogramming or epithelial to mesenchymal transition (EMT) is a key mechanism that drives fibrotic remodelling changes in smokers and patients with COPD. A recent study by Lai et al. further highlights the importance of EMT in smoking-related COPD pathology. The authors identify HB-EGF, an EGFR ligand, as a key driver of EMT and a potential new therapeutic target for the amelioration of EMT and airway remodelling. There are also wider implications in lung cancer prophylaxis, which is another major comorbidity associated with COPD. We consider that improved molecular understanding of the intricate pathways associated with epithelial cell plasticity in smokers and patients with COPD will have major therapeutic implications.