Transforming growth factor beta (TGF-beta) superfamily ligands have important roles in regulating cellular homeostasis, embryonic development, differentiation, proliferation, immune surveillance, angiogenesis, motility, and apoptosis in a cell type and context specific manner. TGF-beta superfamily signaling pathways also have diverse roles in human cancer, functioning to either suppress or promote cancer progression. The TGF-beta superfamily co-receptor, the type III TGF-beta receptor (TbetaRIII, also known as betaglycan) mediates TGF-beta superfamily ligand dependent as well as ligand independent signaling to both Smad and non-Smad signaling pathways. Loss of TbetaRIII expression during cancer progression and direct effects of TbetaRIII on regulating cell migration, invasion, proliferation, and angiogenesis support a role for TbetaRIII as a suppressor of cancer progression and/or as a metastasis suppressor. Defining the physiological function and mechanism of TbetaRIII action and alterations in TbetaRIII function during cancer progression should enable more effective targeting of TbetaRIII and TbetaRIII mediated functions for the diagnosis and treatment of human cancer.