The effective regulation of therapeutic transgenes will in some cases require delivery of their complete genomic loci, to include regulatory sequences such as promoters and introns. To this end, vectors that can accommodate large inserts and shuttle between bacterial and mammalian cells have been developed. On page 1311, Wade-Martins et al. show that such a system can be used to correct a disease phenotype in human cells by delivering a 115 kb genomic transgene on an episomal plasmid. The episome expressed the transgene and remained stable in the cell line for six months.