Recent developments in DNA nanotechnology brought rich structural and functional diversity. However, for DNA nanostructures to perform in a biologically relevant context, obstacles such as nuclease activity and low divalent ion concentrations have to be addressed. For drug delivery or gene therapy applications, ultimately the lipid membrane barriers must be targeted and overcome. In this article, we highlight efforts and achievements in enhancing the stability of DNA nanostructures including chemical modifications, covalent crosslinking and coating with protective layers composed of polymers or lipids. We then review interactions between DNA nanostructures and lipid membranes, which are often mediated by ligands for membrane receptors or hydrophobic domains incorporated into the structure. Finally, we present applications of DNA nanostructures on and in lipid membranes, including higher order assembly, controlling membrane curvature, targeting and arranging membrane proteins in living cells and DNA-based synthetic lipid channels. (C) 2019 Elsevier Ltd. All rights reserved.