More than 1.5 million percutaneous coronary interventions are performed annually. The most important long-term complication is restenosis caused by inflammation, neointimal vascular smooth muscle cell (VSMC) hyperplasia, and excess accumulation of extracellular matrix. Delineating mechanisms that contribute to inflammation, neointimal hyperplasia, and constrictive vascular remodeling will, therefore, improve and expand the options for prophylactic and therapeutic percutaneous coronary interventions for the growing population of patients with arterial disease. See accompanying article on page e9 Hyaluronan is a pericellular and extracellular matrix component of normal vasculature located throughout vessels from the luminal surface of the endothelium, to most prominently in the adventitia. The marked upregulation of hyaluronan production and accumulation in atherosclerotic lesions and in the neointima of restenotic vessels has generated great interest as to its role in vascular disease. Endothelial pericellular hyaluronan promotes leukocyte adhesion and transmigration, whereas hyaluronan binding to CD44 on leukocytes regulates inflammatory gene expression. Platelet-mediated hyaluronan cleavage generates bioactive hyaluronan fragments that stimulate leukocyte production of cytokines and chemokines. Moreover, hyaluronan is involved in the processes underlying the tissue response after vascular injury, in particular, VSMC proliferation and migration. In most cases, the implication of hyaluronan in vascular disease has been based on the circumstantial evidence of elevated hyaluronan levels in vascular lesions or deduced from deleting or blocking hyaluronan receptors (such as CD44 and receptor for HA-mediated motility). Designing approaches to more directly define the role of hyaluronan in vascular disease has been difficult in view of the multitude of synthases (HAS1, HAS2, and HAS3) and multiple hyaluronidases involved in its metabolism. …