The application of gene therapy to liver disease is contingent on the development of an effective gene delivery vehicle. Receptor-mediated endocytosis can be exploited as a means of selective and efficient targeting of gene therapy vectors to hepatocytes. DNA-binding conjugates have been directed to the liver by the attachment of asialoglycoproteins or other ligands for receptors expressed on hepatocytes. Recent studies suggest refinements in this approach through which high transduction rates in vitro may be reproduced in vivo. The intrinsic liver tropism of viral vectors and liposomes can be augmented by the addition of targeting features, as demonstrated in animal models. With further modification, such as the incorporation of hepatotropic elements of the hepatitis viruses or lipoproteins, the next generation of delivery systems may achieve efficient, persistent expression of therapeutic genes in a safe and cell type-specific manner.