The excessive mortality of coronary heart disease is attributed primarily to rupture and thrombotic transformation of the atherosclerotic plaque. Inflammation plays a critical role in plaque destabilization and vulnerability. Inflammation is not confined to the culprit segment but is convincingly widespread in the coronary and remote vascular beds. Systemic inflammatory, thrombotic and hemodynamic factors are relevant to the pathological and clinical outcome. In addition to their fundamental role in thrombosis, there is ample evidence that platelets contribute significantly to promoting plaque inflammation. A new paradigm of unbalanced cytokine-mediated inflammation is emerging, providing diagnostic and therapeutic opportunity for intervention. Amplifying intrinsic anti-inflammatory mechanisms constitutes attractive avenues for future investigation.