Carbon monoxide (CO) has been recognized to act as an atypical neurotransmitter or neuromodulator in the nervous system and to be involved in a wide variety of neuronal activities. Several lines of evidence suggest that CO may play a role through multiple mechanisms in nociception processing. Differential regulation of a family of CO‐generating enzymes, heme oxygenase (HO), contributes mainly to the complexity underlying the role of CO in nociception. This Mini‐Review describes the latest evidence for the role of CO during normal sensory transmission and pathological pain conditions and discusses potential cellular mechanisms by which CO is involved in pathological pain. © 2011 Wiley‐Liss, Inc.