Heme oxygenase-1 (HO-1, also known as HSP32) catalyzes the conversion of heme into biliverdin IXa, carbon monoxide (CO) and iron. HO-2, derived from an entirely different gene, also catalyzes this reaction, but is regulated differently. HO-2 is constitutively expressed with little change in the amount of the protein, except with glucocorticoid treatment. In contrast, HO-1 is present in low amounts in cells, and is induced by a number of stresses, mostly of an oxidative nature, as well as its natural substrate, heme. HO-1 is crucial for survival, since HO-1 de®ciency leads to premature cell death and increased susceptibility to oxidative stress. A growing body of evidence supports the protective function of HO-1 in the cell against oxidative stress. Studies using ``speci®c'' inducers of HO-1, such as hemin or porphyrin, showed better preservation of myocardial function after ischemia/reperfusion, a reduced infarct size in vivo and increased survival after transplantation. More sophisticated experiments, using cardiac-speci®c overexpression of HO-1, also found protection against ischemia and reperfusion injury both in vitro as well as in vivo. Lastly, a decrease of constitutive HO-1, through targeted disruption of the gene, makes the heart more vulnerable to ischemia/reperfusion injury.