The ultimate goal of liver-directed gene therapy for genetic diseases is the stable expression of a therapeutic transgene in a significant proportion of hepatocytes. This article considers the various liver-directed gene transfer procedures studied so far. Performances and limitations of currently available vector systems are discussed with respect to their clinical relevance. Although some improvements have been reported, naked DNA and nonviral gene transfer vectors induce transient expression in only a limited number of cells. Clinical applications of retrovirus-mediated gene transfer are hampered by the need to induce hepatocyte division. First-generation adenovirus vectors are highly efficient; however, they induce an immune response leading to the rapid rejection of transduced cells. Promising new vector systems have emerged, including gutless adenovirus vectors, adeno-associated vectors, and lentivirus vectors. However, these systems are still poorly documented and their relevance to liver-directed gene therapy must be confirmed.