Extracellular ATP is up-regulated in the airways of patients with chronic obstructive pulmonary disease, and may contribute to the pathogenesis of the disease. However, the precise mechanisms are poorly understood. Our objective was to investigate the functional role of the ATP receptor P2X₇ in the pathogenesis of cigarette smoke (CS)–induced lung inflammation and emphysema in vivo. Expression of the P2X₇ receptor (P2X₇R) was measured in lung tissue und immune cells of mice with CS-induced lung inflammation. In a series of experiments using P2X₇ antagonists and genetically engineered mice, the functional role of the P2X₇R in CS-induced lung inflammation was explored. CS-induced inflammation was associated with an up-regulation of the P2X₇R on blood and airway neutrophils, alveolar macrophages, and in whole lung tissue. Selective intrapulmonary inhibition of the P2X₇R reduced CS-induced lung inflammation and prevented the development of emphysema. Accordingly, P2X₇R knockout mice showed a reduced pulmonary inflammation after acute CS exposure. Experiments with P2X₇R chimera animals revealed that immune cell P2X₇R expression plays an important role in CS-induced lung inflammation and emphysema. Extracellular ATP contributes to the development of CS-induced lung inflammation and emphysema via activation of the P2X₇R. Inhibition of this receptor may be a new therapeutic target for the treatment of chronic obstructive pulmonary disease.