Whole organ transplantation is the only clinically effective method of treating fulminant hepatic failure and chronic liver failure due to specific genetic, hepatocellular, and anatomic defects of liver function. However, wider application of liver transplantation is limited by shortage of organ donors, high cost, a relatively high morbidity rate, and need for life long immunotherapy. As a result, investigators have attempted to develop alternative methods to treat liver insufficiency. These ranged from use of plasma exchange to use of detoxification columns and extracorporeal devices loaded with various liver tissue preparations. Several liver support systems were developed in the 1950s and 1960s, but it was not until recently that advances in hepatocyte isolation and culture, improved understanding of hepatocytematrix interactions, availability of new biomaterials, improved hollow fiber technology, and better understanding of flow and mass transport across semipermeable membranes resulted in the development of a new generation of liver assist devices. Some of these devices are being tested in the clinical setting. In this article, the authors review past experience with liver support systems, critically examine the current status of the field by drawing primarily on their own experience, and attempt to speculate on the future direction of liver assist system development.