The discovery that carbon monoxide (CO)-a highly publicized toxic gas molecule-can have powerful benefits and curative effects not only changed how we view CO, but has, with tremendous contradiction, resulted in clinical trials of CO for the treatment of various pathologies. There is sound preclinical evidence that, at a low concentration, CO has benefits in numerous and diverse diseases in rodents, large animals, and humans. CO especially has potential benefits in inflammatory disorders. As CO moves ahead in the clinic, we continue to advance our understanding of how it functions, especially as the number of potential clinical applications expands. CO's mechanisms of action at the cellular level depend on the disease and the experimental focus, but the one constant is that CO reestablishes homeostasis.