Early identification and treatment of the vulnerable plaque, that is, a coronary artery lesion with a high likelihood of rupture leading to an acute coronary syndrome, have gained great interest in the cardiovascular research field. Postmortem studies have identified clear morphological characteristics associated with plaque rupture. Recent advances in invasive and noninvasive coronary imaging techniques have empowered the clinician to identify suspected vulnerable plaques in vivo and paved the way for the evaluation of therapeutic agents targeted at reducing plaque vulnerability. Local treatment of vulnerable plaques by percutaneous coronary intervention and systemic treatment with anti-inflammatory and low-density lipoprotein–lowering drugs are currently being investigated in large randomized clinical trials to assess their therapeutic potential for reducing adverse coronary events. Results from these studies may enable a more patient-tailored strategy for the treatment of coronary artery disease.