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Every cell has a highly sophisticated system for regulating heme levels, which is particularly important with regard to turnover. Heme degradation generates CO and while CO has long been viewed as a metabolic waste product, and at higher concentrations cellularly lethal, we now know that CO is an indispensable gasotransmitter that participates in fundamental physiological processes necessary for survival. Irrefutable preclinical data have resulted in concerted efforts to develop CO as a safe and effective therapeutic agent, but against this notion lies dogma that CO is a poison, especially to the brain. The emergence of this debate is discussed here highlighting the neuroprotective properties of CO through its role on the central circadian clock and ongoing strategies being developed for CO administration for clinical use.