In this issue of Circulation, Rajagopolan et al1 report the first clinical results of a gene therapy approach predicated on transcriptional activation of a patient’s own genes. This represents a second-generation gene therapy methodology for cardiovascular disease and is important for a number of reasons. We have witnessed in the past decade the primary sequencing of the human genome. 2, 3 One of the initial reactions to this milestone accomplishment was surprise at the relatively small number of definitive genes that are encoded by human DNA. Although the exact number is still uncertain, estimates as low as 23 299 have been made. In comparison, the genome of the worm Caenorhabditis elegans encodes approximately 19 000 genes, and the genome of the common fruit fly encodes approximately 18 000 genes, raising the question of how such significant differences in biological complexity and diversity are engendered by so few genes. A complete set of answers to this question is not currently in our grasp, but some crucial aspects are understood and are relevant to the clinical trial discussed here.