Enhancers and insulators are regulatory DNA sequences that can work over a large distance. Efficient action over a distance clearly requires special mechanisms for facilitating communication between a regulatory region and its target. Studies from our laboratory identified DNA supercoiling as primary factor that mediates efficient enhancer-promoter communication over a distance in prokaryotes through a "DNA slithering" mechanism. These studies allowed rational design and construction of an insulator that can block enhancer action over a distance both in vitro and in vivo. Our most recent studies suggest that eukaryotic chromatin structure can support action over a distance using similar principles, but in a mechanistically distinct way.