Occupational exposure to crystalline silica has been linked to pulmonary fibrosis and lung cancer. Surface properties of crystalline silica are critical to the production of oxidant species, chemokines, inflammatory cytokines, and proliferative factors involved in the initiation and progression of silica-induced damage, inflammation, alveolar type II cell hyperplasia, fibroblast activation, and disease. The transcription factors nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) have been shown to play key roles in gene promotion for inflammatory mediators, oncogenes, and growth factors. This review summarizes evidence that in vitro and in vivo exposure to crystalline silica results in activation of NF-kappaB and AP-1. Signaling pathways for activation of these transcription factors are described. In addition, the role of silica-induced reactive oxygen species and nitric oxide in the activation of these signaling events is presented. Last, the generalizability of mechanisms regulating silica-induced pulmonary responses to pulmonary reactions to other occupational particles is discussed.