The transforming growth factor β (TGF-β) superfamily of paracrine and autocrine signaling molecules regulates a vast array of developmental and homeostatic processes and is itself exquisitely regulated. The misregulation of these molecules often results in cancer and other diseases. Here, we focus on new research that explores how TGF-β superfamily signaling is controlled between the secreting cell and the target cell. Regulation can occur upon ligand secretion (in a latent protein complex) and in the creation of signaling gradients. Proteins in the extracellular milieu sequester ligand away from or facilitate ligand binding to receptor serine kinases. Ligands even positively regulate their own negative regulators. Studies of how TGF-β signaling is regulated extracellularly have broadened our understanding of TGF-β pathways, and could provide clues to our understanding and treatment of diseases resulting from misregulation of these pathways.