Acute coronary syndromes (ACS), such as unstable angina, acute myocardial infarction, and sudden cardiac death, are commonly associated with the presence of vulnerable plaques in coronary arteries. Rupture or erosion of vulnerable plaques results in the formation of luminal thrombi due to the physical contact between platelets and thrombogenic elements within the atherosclerotic lesions. Considering the socioeconomic burden of ACS, it is imperative that the scientific community achieves a clear understanding of the multifaceted pathophysiology of vulnerable atheroma to identify accurate prognostic biomarkers and therapeutic targets. The analytical power of modern proteomic technologies could facilitate our understanding of vulnerable plaques and lead to the discovery of novel therapeutic targets and diagnostic biomarkers.