Syndecan-4 provides a mechanical link between the extracellular matrix and the actin cytoskeleton via binding interactions of its cytoplasmic tail. PIP2 binds to the syndecan-4 V-domain – an interaction that stabilizes syndecan-4 multimers against the inner leaflet of the plasma membrane and potentiates PKCα activity. The cytoplasmic tail also interacts with structural and signaling proteins such as CASK, FAK, syndesmos and paxillin. Interactions with these proteins may provide both a mechanical and signaling link to cell surface α5β1 integrins required for focal adhesion and stress fiber formation in cells adherent to fibronectin. Syndecan-4 may also link directly to the actin cytoskeleton through CASK, α-actinin and the FERM family of actin-binding proteins. Less is understood about the functional role of the V-domains of the other syndecan family members. However, the low degree of conservation within this domain amongst the four syndecans suggests distinct roles for the cytoplasmic domains of each of the syndecans in adhesion and signaling.