Stroke is the second cause of mortality in industrialized countries. Atherosclerotic plaque rupture with atheromatous debris distal embolization is the pathogenetic mechanism responsible for cerebrovascular events due to atherosclerotic carotid disease. Plaque composition rather than lesion burden seems to be the determinant factor producing rupture and subsequent thrombosis. Histologic features of vulnerability are : a large lipid core, a thin fibrous cap, and an inflammatory infiltrate rich of monocytes and macrophages. In the clinical practice, it is difficult to predict the risk of experiencing a major cerebrovascular events especially in asymptomatic patients. New invasive techniques such as intravascular ultrasound with termography, optical coherence tomography, fotons spectroscopy and elastography have been developed to detect atherosclerotic lesion tissue composition. However, such techniques are difficult to apply on a large scale basis in primary prevention. On the contrary, new serologic biomarkers such as Pregnancy Associated Plasma Protein-A, Lp-PLA2, Interleukin-6, Interleukin-12, metalloproteinases, lipoprotein-(a), and plaque oxidative products have been recently proposed for screening general and high risk population. The present paper will briefly review the current histologic characteristics of vulnerable plaque and the new imaging tools proposed for its detection, focusing on the most recent serologic biomarkers evaluated in the clinical practice to increase our accuracy in predicting not only the plaque but moreover the patient at risk for an acute cerebrovascular event.