The work by Yao et al reveals that the cyclin-dependent kinase inhibitor p21CIP1/WAF1/SDI1 (designated hereafter as p21), which has been linked to cell cycle growth arrest due to stress or danger cell responses, may modulate alveolar inflammation and alveolar destruction, and thus enlightens our present understanding of how the lung senses injury due to cigarette smoke and integrates these responses with those that activate inflammatory pathways potentially harmful to the lung. Furthermore, the interplay of p21 and cellular processes involving cell senescence and the imbalance of cell proliferation/apoptosis may provide us with a more logical explanation of how p21, acting as a sensor of cellular stress, might have such potent and wide roles in lung responses triggered by cigarette smoke. Molecular switches, ontologically designed for the protection of the host, are now hijacked by injurious stresses (such as cigarette smoke), leading to organ damage. This concept, which is shared with the underlying processes that lead to aging, may also apply to several diseases, including COPD. It is apparent that a novel paradigm is emerging. This paradigm requires that we consider how cigarette smoke alters the molecular controls of lung cell homeostasis, leading to disruption of alveolar maintenance, with the destructive consequences of failure to repair and terminal senescence. These pathobiological processes may provide an alternative or be complementary to the models of unopposed apoptosis and extracellular matrix destruction.