Mechanisms at the basis of coronary plaque instability are still elusive. On the one hand, accumulating data, from clinical and postmortem studies, suggest the role of systemic factors, in particular inflammation, in plaque rupture. On the other hand, local factors, in particular plaque composition, such as a large lipid-rich core and a thin fibrous cap, presence of activated inflammatory cells, presence of plaque neovascularization, and specific apoptotic processes, may contribute to plaque susceptibility to rupture. In addition, other cofactors, such as platelet activation and clotting factors, are involved in the transition from stable to unstable plaque. The authors discuss the possibility that all these factors have a role in the development of acute coronary syndrome: a systemic inflammatory condition with an enhanced coagulation state may activate local hemodynamic, mechanical, and immune reactions leading to intraplaque cells activation, fibrous cap lysis, and thrombus formation.