The Nalp3 inflammasome is essential for the development of silicosis. Inhalation of crystalline silica and asbestos causes progressive pulmonary fibrotic disorders, silicosis and asbestosis, respectively. Alveolar macrophages are believed to initiate these inflammatory responses, but the mechanism remains unclear. This study shows that the inflammatory response and subsequent development of pulmonary fibrosis after silica inhalation depend on the Nalp3 inflammasome. Silica stimulation activates caspase-1 in a Nalp3-dependent manner. Macrophages deficient in Nalp3 inflammasome components cannot secrete proinflammatory cytokines IL-1β and IL-18 in response to silica. Similarly, asbestos activates caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica requires intracellular potassium efflux and reactive oxygen species (ROS) generation. The study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis. Silica crystals are abundant and naturally occurring. Inhalation of silica particles causes silicosis, a chronic interstitial pulmonary disease characterized by fibrosis. Silica and asbestos induce IL-1β secretion in a Nalp3-dependent manner. Silica-induced ROS production is required for Nalp3 inflammasome activation. The chronic fibrosis seen in a murine model of silicosis is dependent on ASC and Nalp3. These findings suggest that silica-induced IL-1β production through the Nalp3 inflammasome plays an important role in the initial inflammatory responses leading to silicosis. Silica induces IL-1β secretion from LPS-primed macrophages. Silica and asbestos induce IL-1β secretion in a Nalp3-dependent manner. Nalp3 and ASC activate caspase-1 in response to various stimuli. Silica-induced IL-1β secretion requires Nalp3. Silica-induced cytotoxicity is independent of Nalp3. Silica-induced IL-1β secretion requires silica internalization, potassium efflux, and ROS generation. Silica-induced ROS are required for Nalp3 inflammasome activation. ASC- and Nalp3-deficient mice have decreased pulmonary pathology in response to inhaled silica. Macrophage production of IL-1β plays an important role in the pathogenesis of silicosis and asbestosis. Nalp3 is the pattern recognition receptor responsible for responding to silica by activating caspase-1 and secreting IL-1β. Mutations in Nalp3 may predispose patients to silicosis and asbestosis. The Nalp3 inflammasome is essential for the development of silicosis. Silica and asbestos induce IL-1β secretion in aThe Nalp3 inflammasome is essential for the development of silicosis. Inhalation of crystalline silica and asbestos causes progressive pulmonary fibrotic disorders, silicosis and asbestosis, respectively. Alveolar macrophages are believed to initiate these inflammatory responses, but the mechanism remains unclear. This study shows that the inflammatory response and subsequent development of pulmonary fibrosis after silica inhalation depend on the Nalp3 inflammasome. Silica stimulation activates caspase-1 in a Nalp3-dependent manner. Macrophages deficient in Nalp3 inflammasome components cannot secrete proinflammatory cytokines IL-1β and IL-18 in response to silica. Similarly, asbestos activates caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica requires intracellular potassium efflux and reactive oxygen species (ROS) generation. The study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis. Silica crystals are abundant and naturally occurring. Inhalation of silica particles causes silicosis, a chronic interstitial pulmonary disease characterized by fibrosis. Silica and asbestos induce IL-1β secretion in a Nalp3-dependent manner. Silica-induced ROS production is required for Nalp3 inflammasome activation. The chronic fibrosis seen in a murine model of silicosis is dependent on ASC and Nalp3. These findings suggest that silica-induced IL-1β production through the Nalp3 inflammasome plays an important role in the initial inflammatory responses leading to silicosis. Silica induces IL-1β secretion from LPS-primed macrophages. Silica and asbestos induce IL-1β secretion in a Nalp3-dependent manner. Nalp3 and ASC activate caspase-1 in response to various stimuli. Silica-induced IL-1β secretion requires Nalp3. Silica-induced cytotoxicity is independent of Nalp3. Silica-induced IL-1β secretion requires silica internalization, potassium efflux, and ROS generation. Silica-induced ROS are required for Nalp3 inflammasome activation. ASC- and Nalp3-deficient mice have decreased pulmonary pathology in response to inhaled silica. Macrophage production of IL-1β plays an important role in the pathogenesis of silicosis and asbestosis. Nalp3 is the pattern recognition receptor responsible for responding to silica by activating caspase-1 and secreting IL-1β. Mutations in Nalp3 may predispose patients to silicosis and asbestosis. The Nalp3 inflammasome is essential for the development of silicosis. Silica and asbestos induce IL-1β secretion in a