Syndecans, a family of transmembrane proteoglycans, are putative integrators of extracellular signals. The interaction of syndecans with extracellular ligands via particular motifs in their heparan sulfate chains, their clustering, association with particular cytoskeletal structures, binding to cytoplasmic effectors, and intracellular phosphorylation represent as many means to bring this role to a successful conclusion. In this review, we will briefly address the characteristics of syndecans as heparan sulfate proteoglycans (HSPGs) and focus mainly on the properties, binding interactions, and potential signaling functions of the cytoplasmic domains of these molecules.