Abstract: Carbon monoxide (CO) is a gaseous transmitter that has received mounting interest because of its therapeutic potentials in the treatment of inflammation, bacterial infection, cancer and so on. However, the clinical application of CO is remarkably hindered by the difficulty in precisely controlling CO concentrations and the targeted delivery of CO to pathological tissues. To circumvent these problems, CO-releasing molecules (CORMs) have been developed and widely used as the alternative of gaseous CO to explore the physiological functions of CO and develop novel therapeutic agents. Unfortunately, conventional CORMs suffered from insufficient stability, short half-life, and poor biodistribution in biological conditions. Intriguingly, the encapsulation of CORMs into polymeric nanoparticles or covalently installation of CORMs to polymeric matrices remarkably improves the stability of CORMs, prolongs the releasing time and optimizes the biodistributions. In this review, we summarize the recent achievements of CO-releasing macromolecules and highlight three approaches used for the fabrication of CO-releasing macromolecules. Also, we envision the potential applications of these macromolecular CO donors and suggest future directions in this field. We hope that more efforts would be devoted to this emerging field to advance the clinical trial of macromolecular CO donors.