Stroke is the leading cause of serious disability in the world and a large number of ischemic strokes are due to thromboembolism from unstable carotid artery atherosclerotic plaque. As it is difficult to predict plaque rupture and surgical treatment of asymptomatic disease carries a risk of stroke, carotid disease continues to present major challenges with regard to clinical decision-making and revascularization. There is therefore an imminent need to better understand the molecular mechanisms governing plaque instability and rupture, as this would allow for the development of biomarkers to identify at-risk asymptomatic carotid plaque prior to disease progression and stroke. Further, it would aid in creation of therapeutics to stabilize carotid plaque. MicroRNAs (miRNAs) have been implicated as key protagonists in various stages of atherosclerotic plaque initiation, development and rupture. Notably, they appear to play a crucial role in carotid artery thromboembolism. As the molecular pathways governing the role of miRNAs are being uncovered, we are learning that their involvement is complex, tissue- and stage-specific, and highly selective. Notably, miRNAs can be packaged and secreted in extracellular vesicles (EVs), where they participate in cell–cell communication. The measurement of EV-encapsulated miRNAs in the circulation may inform disease mechanisms occurring in the plaque itself, and therefore may serve as sentinels of unstable plaque as well as therapeutic targets.