Machine perfusion is an emerging technology in the field of liver transplantation. While machine perfusion has now been implemented in clinical routine throughout transplant centers around the world, a debate has arisen regarding its concurrent effect on the complex hepatic immune system during perfusion. Currently, our understanding of the perfusion-elicited processes involving innate immune cells remains incomplete. Hepatic macrophages (Kupffer cells) represent a special subset of hepatic immune cells with a dual pro-inflammatory, as well as a pro-resolving and anti-inflammatory, role in the sequence of ischemia–reperfusion injury. The purpose of this review is to provide an overview of the current data regarding the immunomodulatory role of machine perfusion and to emphasize the importance of macrophages for hepatic ischemia–reperfusion injury.