Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that acts during inflammatory reactions as the rate-limiting step in the catabolism of heme, yielding equimolar amounts of iron (Fe), biliverdin, and the gas carbon monoxide (CO). Expression of HO-1 regulates inflammatory and immune responses, such as those involved in the rejection of transplanted organs. We will discuss here accumulating evidence supporting the notion that expression of HO-1 in a transplanted organ can prevent its rejection. We will argue that the protective effects exerted by HO-1 are mediated to a large extent by the end products that it generates via the catabolism of heme. Better knowledge of how to enhance these protective effects is likely to help create new therapeutic strategies to improve the outcome of transplanted organs.