Background: Rupture or erosion of an unstable atherosclerotic plaque is the typical pathology and usual cause of acute coronary syndromes. Despite detailed understanding of the processes of lipid accumulation, thinning of the fibrous cap, and inflammation leading to plaque instability, there are no strategies in clinical use that uniquely target the unstable plaque. Objective: A critical review of recent publications on potential therapies that could be used to stabilize unstable plaque. Methods: We searched PubMed, other literature databases, drug development sites, and clinical trial registries to retrieve clinical studies on anti-inflammatory and lipid-modulating therapies that could be used to stabilize unstable atherosclerotic plaque. Results: Multiple experimental targets involving lipid and inflammatory pathways have the potential to stabilize the plaque and expand the armamentarium against coronary artery disease. Randomized clinical trials of darapladib, methotrexate, canakinumab, and colchicine are well advanced to establish if plaque stabilization is feasible and effective in patients with acute coronary syndromes. Conclusions: Although there are still no agents in clinical use for plaque stabilization, there are important advances in understanding plaque instability and several encouraging approaches are being evaluated in Phase III clinical trials. © 2013 Elsevier HS Journals, Inc.