Tissue fibrosis is associated with structural and functional changes that limit blood flow and oxygen availability. In the kidney, tubulointerstitial fibrosis, which leads to progressive destruction of renal tissue and irreversible loss of kidney function, is associated with reduced tissue oxygen levels and activation of hypoxia-inducible factor (HIF) signaling. Although cytoprotective in acute injury models, HIF-1 was found to promote fibrosis in an experimental model of chronic renal injury following unilateral ureteral obstruction. Pharmacological inhibition of lysyl oxidases phenocopied the effects of genetic HIF-1 ablation on cell motility in vitro and on fibrogenesis in vivo, suggesting that lysyl oxidases are important mediators of profibrotic HIF signaling. These findings support the notion that HIF-mediated cellular responses differ under conditions of acute and chronic oxygen deprivation. Under certain conditions, these responses may lead to further tissue destruction by promoting fibrogenesis.