Tenascin-C (TN-C) is a matricellular protein expressed during embryonic development, as well as in wound healing and cancer invasion in various tissues, and may regulate cell behavior and matrix organization during tissue remodeling. In the cardiovascular system, TN-C is transiently expressed at several important steps of embryonic development, playing important roles in the differentiation of cardiomyocytes and in coronary vasculo/angiogenesis. TN-C is sparse in normal adults, but upregulated under pathological conditions such as myocarditis, myocardial infarction, cardiac fibrosis, atherosclerosis, stenotic neointimal hyperplasia, and aneurysm, and is closely associated with tissue injury and inflammation. In view of its specific expression, TN-C could be a realistic and promising biomarker and a target for molecular imaging for the diagnosis of various cardiovascular diseases. TN-C also has diverse functions, including weakening of cell adhesion, up-regulating the expression and activity of matrix metalloproteinases, modulating inflammatory responses, promoting recruitment of myofibroblasts, and enhancing fibrosis. TN-C could exert both harmful and protective effects and might be a therapeutic target as a key molecule in the control of the balance of beneficial and undesirable cellular responses during tissue remodeling.