The transforming growth factor-beta (TGF-beta) signal is manifest through activated heteromeric Smad complex-mediated transcriptional modulation of target genes that translates into diverse, context-specific biologic effects, such as the potent TGF-beta-initiated cytostatic program. The TGF-beta pathway is effectively antagonized through the direct binding and subsequent repression of activated Smad heteromeric complexes by the Ski family of proto-oncoproteins.