Advanced atherosclerotic lesions prone to rupture are characterized by a distinct histomorphology and pathobiology that became in recent years, increasingly related to the process of intraplaque neovascularization. Molecular mechanisms that regulate angiogenesis and that are active in the plaque region may destabilize advanced lesions by promoting microvessel growth and thus providing an entry route for inflammatory cells secondary to the luminal endothelium. In addition, angiogenic factors can also define intraplaque microvessel integrity and endothelial barrier function, determining the prevalence of intraplaque hemorrhaging. Here, we aim to compose a hypothetical model for angiogenic regulation of vulnerable plaque development, based on the evidence of clinical correlation and experimental functional studies that are provided for five of the most well-described angiogenic pathways in the current literature. (c) 2013 Elsevier Inc. All rights reserved.