Damage response pathways triggered by mechanical stress might reasonably be expected to be conserved throughout evolution. However, using a nuclear factor kappa B (NF-kappaB) reporter mouse we show here that this phylogenetically recent transcription factor plays a major role in the response to mechanosensory stress in the mammalian inner ear. The protective action of NF-kappaB is exerted in neither sensory nor non-sensory epithelial cells, but rather in connective tissue cells within the spiral ligament and spiral limbus. In the spiral ligament, predominantly type I fibrocytes are activated following noise exposure, whereas type II fibrocytes are activated following systemic inflammatory stress. Immune-mediated and acoustic trauma-mediated hearing loss syndromes in humans may in part result from the vulnerability of type II and type I fibrocytes to systemic inflammatory stress and acoustic trauma, respectively. Unexpected cell-specific and stress-specific NF-kappaB activation found in the inner ear in this in vivo study suggest that this approach may have wide applications in demonstrating similar specializations of stress responses in other tissues, including the brain.