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Present throughout the vasculature, endothelial cells are essential for blood vessel function and play a central role in the pathogenesis of diverse cardiovascular diseases. Understanding the intricate molecular determinants governing endothelial function and dysfunction is essential to develop novel clinical breakthroughs and improve knowledge. An increasing body of evidence demonstrates that long non-coding RNAS (lncRNAs) are active regulators of the endothelial transcriptome and function, providing emerging insights into core questions surrounding endothelial cell contributions to pathology, and perhaps the emergence of novel therapeutic opportunities. In the present review, we discuss this class of non-coding transcripts and their role in endothelial biology during cardiovascular development, homeostasis, and disease, highlighting challenges during discovery and characterisation and how these have been overcome to date. We further discuss the translational therapeutic implications and the challenges within the field, highlighting lncRNA that support endothelial phenotypes prevalent in cardiovascular disease.