Ischemic cholangiopathy (IC) has been described as the Achilles heel of donation after circulatory death (DCD) liver transplantation. Ischemic cholangiopathy can be defined as diffuse nonanastomotic biliary strictures that occur in a spectrum of clinical and radiologic severity following liver transplantation. Biliary ducts, especially cholangiocytes, seem to be more sensitive to ischemia than hepatocytes; however, the exact mechanism for this is not entirely clear. While IC is observed as a complication of both donation after brain death (DBD) and DCD liver transplantation, initial series with DCD liver transplantation demonstrated IC rates as high as 30% compared to rates of 2–4% seen with DBD liver transplantation. Several distinct radiologic patterns of IC have been described, which are associated with different clinical courses; these include diffuse necrosis, multifocal progressive, confluence dominant, and the minor form. There is growing evidence that suggests there is a profound reduction in the rate of IC following DCD liver transplantation when in situ and ex situ perfusion technologies are utilized. In situ and ex situ perfusion technologies mitigate the risk of IC by restoring oxygen delivery, preventing bile duct epithelial injury, reducing oxidative stress, improving microvascular flow, and supporting metabolic recovery. Treatment of IC can be difficult given the often diffuse multifocal lesions of the biliary tree. Initial therapy primarily focuses on addressing biliary obstruction and treatment of infection (cholangitis). While milder cases of IC can sometimes be successfully managed with percutaneous or endoscopic drainage and stenting, more severe cases will often ultimately require retransplantation. The present chapter provides a thorough overview of IC and provides both proposed treatment options as well as preventative strategies.