The liver offers specific opportunities, as well as challenges, as a target for cell transplantation and gene therapy. Hepatocyte transplantation and hepatocyte-directed gene therapy are mutually augmenting complementary strategies that are rapidly developing for the treatment of inherited and acquired disorders. Both non-viral and viral vectors are being rapidly improved for exploiting the advantages and overcoming the challenges of liver-directed gene therapy. Rapid development in these areas suggests that vectors that will be used a decade from now have not yet been developed. Nevertheless, hepatocyte transplantation already has been successful in ameliorating at least some inherited liver diseases, and it is safe to state that successful liver-directed gene therapy will be achieved during the early years of the new millennium. The nine articles in this issue of the Seminars review the promise and limitations of the current methods of hepatocyte transplantation and liver-directed gene therapy and attempt to provide a glimpse of the anticipated developments.