The heme oxygenase (HO)/carbon monoxide (CO) system is a physiological feedback loop orchestrating various cell-protective effects in response to cellular stress. The therapeutic use of CO is impeded by safety challenges as a result of high CO-Hemoglobin formation following non-targeted, systemic administration jeopardizing successful CO therapies as of this biological barrier. Another caveat is the use of CO-Releasing Molecules containing toxicologically critical transition metals. An emerging number of local delivery approaches addressing these issues have recently been introduced and provide exciting new starting points for translating the fascinating preclinical potential of CO into a clinical setting. This review will discuss these approaches and link to future delivery strategies aiming at establishing CO as a safe and effective medication of tomorrow.