Intestinal transplantation has become an established therapeutic option that provides improved quality of life to patients with end-stage intestinal failure when total parenteral nutrition fails. Whereas this challenging life-saving intervention has shown exceptional growth over the past decade, illustrating the evolution of this complex and technical procedure from its preclinical origin in the mid-20th century to become a routine clinical practice today with several recent innovations, its success is hampered by multiple hurdles including technical challenges such as surgical manipulation during intestinal graft procurement, graft preservation and reperfusion damage, resulting in poor graft quality, graft rejection, post-operative infectious complications, and ultimately negatively impacting long-term recipient survival. Therefore, strategies to improve current intestinal transplantation protocol may have a significant impact on post-transplant outcomes. Carbon monoxide (CO), previously considered solely as a toxic gas, has recently been shown to be a physiological signaling molecule at low physiological concentrations with therapeutic potentials that could overcome some of the challenges in intestinal transplantation. This review discusses recent knowledge about CO in intestinal transplantation, the underlying molecular mechanisms of protection during intestinal graft procurement, preservation, transplantation and post-transplant periods. A section of the review also discusses clinical translation of CO and its challenges in the field of solid organ transplantation.