Despite recent progress in critical care, sepsis remains a serious problem with high rate of mortality. Although the pathophysiology of sepsis has not been fully elucidated, oxidative stress associated with excessive systemic inflammation plays an important role in its pathogenesis. Oxidative stress conditions principally involving transcriptional activation of genes encoding proteins that participate in the defense against oxidative tissue injuries. One of them is heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, as well as the 32 kDa heat shock protein. HO-1 induction has been shown to confer protection, while its abrogation accelerates oxidative tissue injuries. In this review, recent findings concerning the role of HO-1 as a protective response against oxidative stress conditions in sepsis are summarized.