Increased understanding of the genetic basis of human disease has led to a number of potential gene-based therapies for various medical and surgical disorders. The development of efficient methods for delivering genes to mammalian cells in vitro has increased the potential clinical utility of gene-based therapies; however, a major focus of research has been more efficient delivery to appropriate target cells, in vivo as well as in vitro, to establish gene therapy as an effective clinical modality for common disorders. Despite substantial progress, a number of critical technical issues to enhance and optimize not only gene transfer but also gene expression must be resolved. These future technological developments will be essential for the widespread clinical implementation of gene-based therapy.