Transforming growth factor-β (TGF-β) represents an evolutionarity conserved family of secreted factors that mobilize a complex signaling network to control cell fate by regulating proliferation, differentiation, motility, adhesion, and apoptosis. TGF-β promotes the assembly of a cell surface receptor complex composed of type I (TβRI) and type II (TβRII) receptor serine/threonine kinases. In response to TGF-β binding, TβRII recruits and activates TβRI through phosphorylation of the regulatory GS- domain. Activated TβRI then initiates cytoplasmic signaling pathways to produce cellular responses. SMAD proteins together constitute a unique signaling pathway with key roles in signal transduction by TGF-β and related factors. Pathway-restricted SMADs are phosphorylated and activated by type I receptors n response to stimulation by ligand. Once activated, pathway- restricted SMADs oligomerize with the common-mediator Smad4 and subsequently translocate to the nucleus. Genetic analysis in Drosophila melanogaster and Caenorhabditis elegans, as well as TβRII and SMAD mutations in human tumors, emphasizes their importance in TGF-β signaling. Mounting evidence indicates that SMADs cooperate with ubiquitous cytoplasmic signaling cascades and nuclear factors to produce the full spectrum of TGF-β responses. Operating independently, these ubiquitous elements may influence the nature of cellular responses to TGF-β. Additionally, a variety of regulatory schemes contribute temporal and/or spatial restriction to TGF-β responses. This report reviews our current understanding of TGF-β signal transduction and considers the importance of a cooperative signaling paradigm to TGF-β-mediated biological responses.