Carbon monoxide (CO) is an endogenously generated gas that may play an important physiological role in the regulation of vascular tone. The CO-induced vasorelaxation, as a result of a direct action on vascular smooth muscles, has been demonstrated in many cases. Three major cellular mechanisms are proposed to explain the vasorelaxing effect of CO. These include the activation of soluble guanylyl cyclase, stimulation of various types of K channels, and inhibition of the cytochrome P450 dependent monooxygenase system in vascular smooth muscle cells. An interaction between CO and nitric oxide may also significantly contribute to the fine tuning of vascular tone. Furthermore, alterations in either the endogenous production of CO or the vascular responsiveness to CO have been encountered in several pathophysiological situations. A better understanding of the vascular effects of CO and the underlying cellular and molecular mechanisms will pave the way for the establishment of the role played by CO in vascular physiology and pathophysiology.