Cell surface heparan sulfate proteoglycans (HSPG) can be divided generally into two gene families: syndecans and glypicans. While the glypicans are GPI-anchored, the syndecans are transmembrane-anchored with distinct ecto-domains and short cytoplasmic tails. Syndecans bind a range of soluble ligands including growth factors as well as insoluble ligands such as the extracellular matrix protein fibronectin. Indeed, in combination with b1 integrins, syndecan-4-dependent interactions with fibronectin lead to the assembly of focal adhesions and actin stress fibers. Given the fact that syndecan-4 is upregulated in endothelial cells and fibroblasts during wound healing, it has been speculated that this cell-surface HSPG might participate in tissue repair. Echtermeyer and colleagues provide the first characterization of wound repair in syndecan-4 knockout mice. Interestingly, homozygotes as well as heterozygotes for the disrupted gene display marked defects in wound repair and angiogenesis. Of some surprise, in vitro analysis of syndecan-4-deleted fibroblasts demonstrate normal focal adhesion assembly, stress fiber formation and contractility. Likewise, the cells respond to FGF-2 normally despite the ability of syndecan-4 to act as a co-receptor for the growth factor. The -/- cells do, however, display a reduced role of migration in vitro, but in contrast to the in vivo state, only the -/- fibroblasts (and not the +/- fibroblasts) are affected. More telling defects in cell-matrix and growth factor interactions may be compensated for by other members of the syndecan family. These studies not only highlight the importance of syndecan-4 in wound repair, but also underscore the limited ability of in vitro analyses to predict complex behavior in vivo.