Early identification of vulnerable, rupture-prone atherosclerotic plaques with the optimal goal of cardiovascular event prevention is a field of vigorous research. Despite the advances in imaging modalities and the in vivo identification of many characteristics of vulnerability, few of these plaques actually rupture and even fewer lead to clinical events, questioning the predictive value of the above techniques in clinical practice. Factors causing the higher local vulnerability of the culprit plaque within a prothrombotic environment of widespread inflammation are generally unknown. Newly recognized local features, including microcalcifications and biomechanical factors, seem to contribute. In this review article, we target on new mechanisms, implicated in vulnerable plaque formation and rupture, analysing their potential clinical value.