The transforming growth factor-β (TGF-β) superfamily is a large group of structurally related growth factors that play prominent roles in a variety of cellular processes. The importance and prevalence of TGF-β signaling are also reflected by the complex network of check points that exist along the signaling pathway, including a number of extracellular antagonists and membrane-level signaling modulators. Recently, a number of important TGF-β crystal structures have emerged and given us an unprecedented clarity on several aspects of the signal transduction process. This review will highlight these latest advances and present our current understanding on the mechanisms of specificity and regulation on TGF-β signaling outside the cell.