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Atherosclerosis is a complex inflammatory disease of the vessel wall involving the interplay of multiple cell types including vascular smooth muscle cells, endothelial cells, and macrophages. Large-scale genome-wide association studies (GWAS) and the advancement of next generation sequencing technologies have rapidly expanded the number of long non-coding RNA (lncRNA) transcripts predicted to play critical roles in the pathogenesis of the disease. In this review, we highlight several lncRNAs whose functional role in atherosclerosis is well-documented through traditional biochemical approaches as well as those identified through RNA-sequencing and other high-throughput assays. We describe novel genomics approaches to study both evolutionarily conserved and divergent lncRNA functions and interactions with DNA, RNA, and proteins. We also highlight assays to resolve the complex spatial and temporal regulation of lncRNAs. Finally, we summarize the latest suite of computational tools designed to improve genomic and functional annotation of these transcripts in the human genome. Deep characterization of lncRNAs is fundamental to unravel coronary atherosclerosis and other cardiovascular diseases, as these regulatory molecules represent a new class of potential therapeutic targets and/or diagnostic markers to mitigate both genetic and environmental risk factors.