Thrombospondin 1 (TSP1) plays major roles in both physiologic and pathologic tissue repair. TSP1 through its type 1 repeats is a known regulator of latent TGF-β activation and plays a role in wound healing and fibrosis. Binding of the TSP N-terminal domain to cell surface calreticulin in complex with LDL-receptor related protein 1 stimulates intermediate cell adhesion, cell migration, anoikis resistance, collagen expression and matrix deposition in an in vivo model of the foreign body response. There is also emerging evidence that TSP EGF-like repeats alter endothelial cell-cell interactions and stimulate epithelial migration through transactivation of EGF receptors. The mechanisms underlying these functions of TSP1 and the implications for physiologic and pathologic wound repair and fibrosis will be discussed. © 2012 International Society of Matrix Biology.