The maintenance of the alveolar structure is required throughout life. To accomplish this goal, alveolar cells, including endothelial, epithelial, and fibroblastic cells, provide key molecules with broad survival and antiapoptotic effects. These complex interactions are disrupted by cigarette smoke, leading to emphysema. Smoke imposes an environmental stress to the lung with the activation of "sensor-like" molecular signaling. Activation of RTP801, leading to mTOR inhibition, is paradigmatic of these responses. The accumulation of cellular damage, with the generation of endogenous mediators of inflammation, may proceed toward an aging phenotype. These alterations may impose significant challenges to cell-based regenerative or pharmacological therapies.