Stroke is the second most common cause of death in developed countries. Carotid plaque disruption and distal embolization of atheromatous debris are the most common pathogenic mechanisms for cerebral ischemia from carotid atherosclerotic disease. Morphologic composition of the atherosclerotic plaque, rather than the stenotic severity, appears to be central in determining the risk of both plaque rupture and subsequent thrombosis. Histologic features of vulnerable plaques include a large lipid core, a thin fibrous cap, intraplaque hemorrhage, and an increased number of inflammatory cells, mostly monocyte-macrophages. Due to the catastrophic implications of thrombus formation and embolization on the arterial plaque, detection before major neurologic events occur is now a major goal of cardiovascular clinicians and researchers. New detection imaging techniques such as intravascular thermography, optical coherence tomography, photonic spectroscopy, and elastography have been developed in order to document atherosclerotic lesion composition. This review will focus on the new possibilities under investigation for vulnerable atherosclerotic carotid plaque detection by means of the serologic markers of plaque instability. New markers, such as pregnancy-associated protein A, P-selectin, interleukin-6 and interleukin-12, metalloproteinases, lipoprotein(a), and oxidation products have been reviewed. Most of the promising serologic markers in this article are still in a nascent phase of development and remain to be validated in clinical settings. However, these biohumoral markers, and their potential combination of techniques, may hold promise for the future characterization of the vulnerable plaque and moreover of the vulnerable patient.