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Endothelial cells (ECs) mediate several biological functions that are relevant to atherosclerosis and coronary artery disease (CAD), regulating an array of vital processes including vascular tone, wound healing, reactive oxygen species, shear stress response, and inflammation. Although it is not yet known which of these functions is causally linked with CAD development and/or progression, genome-wide association studies (GWASs) have implicated over 400 loci associated with CAD risk, among which several have demonstrated EC-relevant functions. Given the arduous process of mechanistically interrogating single loci to CAD, high-throughput variant characterization methods - including pooled CRISPR screens - offer exciting potential to rapidly accelerate the discovery of bona fide EC-relevant genetic loci. These discoveries will in-turn broaden the therapeutic avenues for CAD beyond lipid lowering and behavioral risk modification to include EC-centric modalities of risk prevention and treatment.