Liver transplantation has become a well-recognized therapy for hepatic failure resulting from acute or chronic liver disease. It also plays a role in the treatment of certain inborn errors of metabolism that do not directly injure the liver. In fact, the liver maintains a central role in many inherited and acquired genetic disorders. There has been a considerable effort to develop new and more effective gene therapy approaches, in part, to overcome the need for transplantation as well as the shortage of donor livers. Traditional gene therapy involves the delivery of a piece of DNA to replace the faulty gene. More recently, there has been a growing interest in the use of gene repair to correct certain genetic defects. In fact, targeted gene repair has many advantages over conventional replacement strategies. In this review, we will describe a variety of viral and nonviral strategies that are now available to the liver. The ever-growing list includes viral vectors, antisense and ribozyme technology, and the Sleeping Beauty transposon system. In addition, targeted gene repair with RNA/DNA oligonucleotides, small-fragment homologous replacement, and triplex-forming and single-stranded oligonucleotides is a long-awaited and potentially exciting approach. Although each method uses different mechanisms for gene repair and therapy, they all share a basic requirement for the efficient delivery of DNA.