AbstractHeme oxygenase is an essential enzyme in heme catabolism that cleaves heme to form biliverdin, releasing carbon monoxide and iron. In mammals, biliverdin is subsequently converted to bilirubin by biliverdin reductase. There are two isozymes of heme oxygenase: heme oxygenase‐1 (HO‐1) and heme oxygenase‐2 (HO‐2), each of which is encoded by a separate gene. Both isozymes share a significant similarity in amino acid sequence and catalyze heme breakdown under similar conditions. However, both enzymes are regulated in distinct manners: specifically, HO‐1 is inducible by various environmental factors including its own substrate heme, while HO‐2 is not inducible at all. Moreover, there has been remarkable progress concerning the physiological roles of the heme catabolites carbon monoxide (CO) and bilirubin, which had previously been considered mere toxic waste products. However, CO was suggested to function as a potential signaling gas, and bilirubin was shown to be an effective radical scavenger under physiological conditions. Thus, the inducibility of HO‐1 may represent an important biological response. In this review, the general properties of heme oxygenase are briefly described with emphasis on the current findings regarding the regulation of heme oxygenase ge