There is a strong need for biomarkers to identify patients at risk for future cardiovascular events related with progressive atherosclerotic disease. Ideally, increasing knowledge of the mechanisms of atherosclerotic plaque destabilization should be translated in clinical practice. Currently, the following commonly followed strategies can be identified with the objective to detect either the local vulnerable plaque that is prone to rupture and gives rise to a thrombotic occlusion, or the systemic vulnerable patient, who has a high probability to suffer from an adverse clinical event. On the one hand, studies are ongoing to determine local atherosclerotic plaque characteristics to predict future local plaque rupture and subsequent vascular thrombosis. Newly developed imaging modalities are being developed and validated to detect these plaques in vivo. On the other hand, systemic approaches are pursued to discover serum biomarkers that are applicable to define patients at risk for future cardiovascular events. We propose a third original approach that is optional but yet unexplored, that is, to use local plaque characteristics as a biomarker not just for local plaque destabilization but for future cardiovascular events due to plaque progression in any vascular system. This review aims to provide an overview of the current standings of the identification of the vulnerable plaque and the vulnerable patient.