Tissue homeostasis depends on spatially and temporally controlled expression of multifunctional adhesive glycoproteins and their cellular counter receptors, and on a tight regulation of proteolytic enzyme systems. The adhesive glycoprotein vitronectin (Vn) not only regulates adhesive events, but also controls a number of these proteolytic enzyme cascades, including the complement, coagulation, and fibrinolytic systems. However, understanding of the biological functions of this molecule is complicated due to it's conformationally lability and its tendency to self-associate. While plasma Vn is monomeric and lacks exposure of conformationally sensitive epitopes, platelet and tissue-associated Vn are believed to be conformationally altered and multimeric. The latter forms express a functional repertoire distinct from plasma Vn. While little Vn immunoreactivity is detectable in most normal tissues, increased depositions of Vn have been observed in areas of tissue injury and necrosis. Tissue Vn was believed to be plasma-derived, but recent studies indicate that extrahepatic cells have the biosynthetic potential to produce Vn and that its synthesis can be regulated under inflammatory conditions. Here, the constitutive and regulated expression of Vn, its locations in tissues and interaction with other matrix molecules are reviewed and their implications for the functions of this molecule are discussed.