Comprehensive analysis of mammalian transcriptomes has surprisingly revealed that a major fraction of the RNAs produced by mammalian cells and tissues is comprised of long non-coding RNAs (IncRNAs). Such RNAs were previously disregarded as useless, but recent functional studies have revealed that they have multiple regulatory functions. A large subset of these IncRNAs are antisense to protein-coding genes; such RNAs are particularly attractive to researchers because their functions are better understood than other IncRNAs and their action can be easily modulated and engineered by modifying the antisense region. We discuss various aspects of regulation by antisense RNAs and other small nucleic acids and the challenges to bring these technologies to gene therapy. Despite several remaining issues related to delivery, RNA stability, side effects, and toxicity, the field is moving quickly towards future biotechnological and health applications. Therapies based on IncRNAs may be the key to increased cell-specificity of future gene therapies. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.