Clinical experience and pathologic evidence strongly support an association between PSC and cholangiocarcinoma. Cholangiocarcinoma arises in 5 to 10% of patients with preexisting PSC and can also present in a synchronous fashion with PSC. Cholangiocarcinoma complicating PSC is heralded by rapid clinical deterioration with progressive jaundice, weight loss, and abdominal discomfort. These tumors have been most frequently detected at an advanced stage, which precludes potentially curative resection. Liver transplantation for locally advanced and incidentally discovered tumors has been fraught with frequent tumor recurrence. Regardless of therapy, the prognosis for patients with cholangiocarcinoma complicating PSC has been uniformly poor. There is a clear need for heightened clinical awareness, methods for earlier detection, and effective therapy for patients with cholangiocarcinoma complicating PSC.