Studies of heme-containing gas sensor proteins have revealed a novel function for heme, which acts as an active site for sensing the corresponding gas molecule of a physiological effector. Heme-based O(2), NO, and CO sensor proteins have now been described in which these gas molecules act as a signaling factor that regulates the functional activity of the sensor proteins. CooA is a CO-sensing transcriptional activator found in the photosynthetic bacterium Rhodospirillum rubrum. The binding of CO to the heme group stimulates the transcriptional activator activity of CooA. The mechanisms of CO sensing by CooA and CO-dependent activation of CooA have now been analyzed by both molecular biological and spectroscopic studies and are discussed in this Account.