It has become accepted that nitric oxide serves important functions in biological systems as a second messenger. Another diatomic gaseous molecule, carbon monoxide (CO), is also rapidly gaining acceptance as a signaling agent. Some of the activities of CO are analogous to those of nitric oxide in the vascular system and the brain, but CO also behaves in novel ways. Like nitric oxide, CO is capable of activating soluble guanylyl cyclase. This mechanism of CO signaling is important in vasodilation and neurotransmission. There is growing evidence, however, that CO also acts independently of soluble guanylyl cyclase. CO has been shown to protect against septic shock and lung injury in animal models, and the mitogen-activated protein kinase system appears to mediate this cytoprotective effect. Although much remains to be elucidated about the mechanisms of cell signaling by CO, the pace of discovery in this field is making the picture clearer with every passing day.