PURPOSE OF REVIEW Hemoglobin and its scavenger proteins haptoglobin and hemopexin (Hx) associate with HDL and influence the inflammatory properties of HDL. Moreover, HDL from Hx-null mice is proinflammatory. In addition, Hx deficiency is implicated in a number of other inflammatory diseases such as septic shock and experimental autoimmune encephalomyelitis. This article highlights studies that demonstrate novel insights into the physiological protective role of Hx in inflammatory diseases. RECENT FINDINGS Recent studies demonstrate that Hx-dependent uptake of extracellular heme leads to the deactivation of Bach1 repression leading to the transcriptional activation of antioxidant heme oxygenase-1 gene. Levels of circulating Hx have been implicated in the prognosis for patients with septic shock. In addition, Hx therapy has been shown to be beneficial in cardiovascular disease, cerebral ischemic injury, and experimental autoimmune encephalomyelitis. SUMMARY These studies suggest that heme scavenging is a major mechanism by which Hx defends against oxidative stress and related inflammatory disorders. Hx therapy may provide a novel protective role against heme and oxidative stress-mediated inflammatory conditions including atherosclerosis.