Heme oxygenase-1 (HO-1) is a ubiquitous inducible stress-response enzyme that plays a central role in tissue homeostasis, in protection against oxidative stress, and in the pathogenesis of disease. Kim et al. report a novel transgenic mouse that lacks the endogenous HO-1 gene but contains the human HO-1 gene with all its regulatory elements. These transgenic animals overexpress HO-1 in basal conditions but maintain HO-1 inducibility, protecting the kidney against glycerol- and cisplatin-induced nephrotoxicity.