Despite significant strides to mitigate the complications of acute coronary syndrome (ACS), this clinical entity still represents a major global health burden. It has so far been well-established that most of the plaques leading to ACS are not a result of gradual narrowing of the vessel lumen, but rather a result of sudden disruption of vulnerable atherosclerotic plaques. As most of the developed imaging modalities for vulnerable plaque detection are invasive, multiple biomarkers were proposed to identify their presence. Owing to the pivotal role of lipids and inflammation in the pathophysiology of atherosclerosis, most of the biomarkers originated from one of those processes, whereas recent advancements in molecular sciences shed light on the use of microRNAs. Yet, at present there are no clinically implemented biomarkers or any other method for that matter that could non-invasively, yet reliably, diagnose the vulnerable plaque. Hence, in this review we summarized the available knowledge regarding the pathophysiology of plaque instability, the current evidence on potential biomarkers associated with plaque destabilization and finally, we discussed if search for biomarkers could one day bring us to non-invasive, cost-effective, yet valid way of diagnosing the vulnerable, rupture-prone coronary artery plaques.