TGF-β signaling is both regulated and mediated by signaling co-receptors. Several TGF-β co-receptors have been identified including endoglin (CD105), the type III TGF-β receptor (TβRIII, betaglycan), neuropilin-1/2, syndecan-2, CD109, and LRP1. These co-receptors serve diverse functions including the regulation of ligand acceβ to other TGF-β receptors and receptor trafficking. The TGF-β co-receptors can also signal directly. The TGF-β co-receptors are broadly expreβed, have eβential roles in embryonic development, and are frequently altered during disease progreβion. TGF-β co-receptors regulate cancer initiation and progreβion through effects on cell growth, migration, invasion, proliferation, and angiogenesis. In addition to their roles in cancer, these co-receptors are dysregulated during development, in vascular disease and fibrotic disorders. Collectively, the TGF-β co-receptors influence disease biology through complex mechanisms involving the regulation of growth factor-dependent and independent signaling events as well as through interactions with diverse scaffolding protein partners.