Recent sequence-based technologies have revealed thousands of long non-coding RNAs (lncRNAs) regulate gene expression by acting at epigenetic, transcriptional, and post-transcriptional levels. We previously identified >1000 lncRNAs in human pancreatic beta cells and islets, and showed that many are induced during beta cell differentiation, and show a very restricted pattern of expression across tissues. Several islet lncRNAs were dynamically regulated by changes in glucose concentrations, suggesting that they might be relevant to adaptive beta cell responses, while some examples were deregulated in islets from donors with Type 2 diabetes. These interesting features warrant a need to rigorously test whether lncRNAs play a functional role in beta cells. I will present studies in which lncRNAs have been perturbed to test their role in gene regulation and function. The analysis of functional non-coding beta cell genes can potentially shed new light into developmental and cellular mechanisms, provide approaches to program cells for regenerative therapies, and uncover new causes of human disease.