Background: Carotid disease is an important cause of ischemic stroke. Traditionally, therapeutic efforts in carotid disease have been aimed at identifying carotid stenosis in symptomatic patients and treating high-grade stenosis. New research suggests that identifying the vulnerable plaque in symptomatic or asymptomatic patients may be a more rational approach for the prevention of ischemic events. Methods: The author reviews some key references on identification of the vulnerable carotid plaque using different imaging modalities and using biochemical markers. The potential applications of such tools are discussed. Results: Carotid ultrasound, computed tomography, and magnetic resonance angiography can help identify plaque features associated with the so-called vulnerable plaque. Carotid ultrasound is the most widely studied modality and the easiest to perform and interpret. Concomitant measurement of serum biochemical markers associated with atherosclerosis, inflammation, and thrombosis may help identify the vulnerable carotid plaque. Conclusions: A multimodal approach to studying the carotid plaque appears to be a promising tool in identifying vulnerable carotid plaques. The current literature suggests that in addition to the degree of stenosis other imaging and biochemical findings have important clinical significance.