Chronic obstructive pulmonary disease is characterized by dramatic alterations in lung architecture associated to an exaggerated inflammatory process, alveolar epithelial cell apoptosis, endothelial dysfunction and extracellular matrix destruction due to a protease and anti-protease imbalance. In addition a significant inflammatory spillover into systemic circulation has been suggested to be responsible for a wide range of fatal comorbidities. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will fulfill the unmet need of modulating both local and systemic inflammation and at the same time accelerate alveolar epithelial and endothelial turnover intervening into disease natural course and not only relieving patient's symptoms. Regenerative medicine based on stem cells properties represents one promising option with several fruitful therapeutic applications in patients with COPD. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administrated stem cells within the COPD lung as well as the mechanisms regulating activation of resident progenitor cells. The above evidence coupled with the rather disappointing results emerging from the first stem cell clinical trials in COPD patients underline the need for careful study design by setting realistic goals to assess efficacy such as biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn. © 2013 Bentham Science Publishers.