Heme oxygenase-1 (HO-1) is a microsomal enzyme involved in the degradation of heme, resulting in the generation of biliverdin, iron, and carbon monoxide. Recent attention has focused on the biologic effects of product(s) of this enzymatic reaction that have important antioxidant, anti-inflammatory, and cytoprotective functions. Induction of HO-1 occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli, including heme, hydrogen peroxide, cytokines, growth factors, heavy metals, nitric oxide, and oxidized LDL. HO-1 has been implicated in several clinically relevant disease states, including transplant rejection, hypertension, acute renal injury, atherosclerosis, and others. Previous studies indicate a protective role for HO-1 in heme and non-heme-mediated models of acute renal injury using chemical inducers and inhibitors of HO-1. Studies in HO-1 knockout mice further corroborate these observations, highlighting the important role of HO-1 in the pathophysiology of acute renal injury. Expression of HO-1 has been linked to prolonged xenograft survival and is important in transplant rejection as well. More recently, the first known case of human HO-1 deficiency was reported with several phenotypical similarities to the mouse HO-1 knockout. The role of HO-1 has extended far beyond its initial description as an enzyme involved in heme degradation to being an important mediator in modulating adaptive and protective responses not only in renal injury, but in other organ systems as well.