Emerging data suggest that intraplaque hemorrhage is critical in promoting atherosclerotic lesion instability. Because red blood cell membranes are a rich source of free cholesterol and accumulated red blood cells within plaques promote inflammation, intraplaque hemorrhage is associated with expansion of the necrotic core. Plaque hemorrhage results from the development of immature neointimal vasa vasorum. Therefore, it is proposed that molecular therapies designed to eliminate pathologic neovascularization within developing lesions will interrupt the process of hemorrhage and decrease the rate of necrotic core expansion. The elimination of intraplaque neovascularization would involve targeting of pre-existing and new vessel development. The concept of vascular regression has met some success in other neovascular-dependent diseases, including macular degeneration and malignancies. The efficacy of this novel approach is dependent on gaining critical knowledge of the environment required to support development and maturation of the vasa vasorum within varying plaque types. A multitargeted approach involving selective local antiangiogenic agents should contribute to prevention of plaque progression and its clinical consequences.