Carbon monoxide (CO) is a gaseous product generated by heme oxygenase (HO). Because of its nature to bind to the metal-centered prosthetic groups, the gas might bind to multiple target proteins to regulate varied biological functions. Previous studies revealed that stress-inducible levels of CO from HO-1 modulate function of different heme proteins or enzymes through binding to their prosthetic ferrous heme to regulate biological function of cells and organs including hepatobiliary systems. On the other hand, CO derived from constitutive HO-2 appeared to play house-keeping roles for microvascular perfusion or cellular homeostasis: such CO-directed target macromolecules include soluble guanylate cyclase, cytochromes P450 and NO synthase. Our recent studies revealed roles of cystathionine β-synthase in vivo for a novel CO-sensitive regulator of metabolic system that is a determinant of endogenous H 2S, another gaseous mediator. This chapter reviews the intriguing networks of metabolic regulatory mechanisms constituted by different gaseous mediators and their medical implications.