AbstractThe concept that the mammalian glycoprotein vitronectin acts as a biological ‘glue’ and key controller of mammalian tissue repair and remodelling activity is emerging from nearly 50 years of experimental in vitro and in vivo data. Unexpectedly, the vitronectin‐knockout (VN‐KO) mouse was found to be viable and to have largely normal phenotype. However, diligent observation revealed that the VN‐KO animal exhibits delayed coagulation and poor wound healing. This is interpreted to indicate that VN occupies a role in the earliest events of thrombogenesis and tissue repair. VN is the foundation upon which the thrombus grows in an organised structure. In addition to sealing the wound, the thrombus also serves to protect the underlying tissue from oxidation, is a reservoir of mitogens and tissue repair mediators, and provides a provisional scaffold for the repairing tissue. In the absence of VN (e.g., VN‐KO animal), this cascade is disrupted before it begins. A wide variety of biologically active species associate with VN. Although initial studies were focused on mitogens, other classes of bioactives (e.g., glycosaminoglycans and metalloproteinases) are now also known to specifically interact with VN. Although some interactions are transient, others are long‐lived and often result in multi‐protein complexes. Multi‐protein complexes provide several advantages: prolonging molecular interactions, sustaining local concentrations, facilitating co‐stimulation of cell surface receptors and thereby enhancing cellular/biological responses. We contend that these, or equivalent, multi‐protein complexes facilitate VN polyfunctionality in vivo. It is also likely that many of the species demonstrated to associate with VN in vitro, also associate with VN in vivo in similar multi‐protein complexes. Thus, the predominant biological function of VN is that of a master controller of the extracellular environment; informing, and possibly instructing cells ‘where’ to behave, ‘when’ to behave and ‘how’ to behave (i.e., appropriately for the current circumstance). © 2013 IUBMB Life, 65(10):807‐818, 2013