The mechanisms underlying the progressive fibrosis that characterises end-stage renal disease in vivo remain to be established but hypoxia, as a result of microvascular injury and loss, has been suggested to play an important role. In support of this hypothesis, in vitro studies show that hypoxia (1% O<sub>2</sub>) induces a fibrogenic phenotype in human renal tubular endothelia, interstitial fibroblasts and microvascular endothelial cells, simultaneously increasing extracellular matrix (ECM) production and decreasing turnover via effectors on matrix-degrading enzymes and their inhibitors. The effects of hypoxia on ECM metabolism are independent of hypoxia-induced growth factors and are mediated by a haem-protein sensor and activation of both protein kinase C- and tyrosine kinase-mediated signal transduction pathways. De novo gene transcription is regulated by both hypoxia-inducible factor-1-dependent and -independent mechanisms. Further understanding of the molecular mechanisms by which decreased oxygen alters expression of genes involved in ECM metabolism in renal cells may provide new insights into the pathogenesis of fibrosis and identify novel avenues for intervention.