The article reviews the role of non-Smad signaling proteins in TGF-β signaling pathways. It highlights three general mechanisms by which non-Smad proteins contribute to physiological responses to TGF-β: (1) directly modifying Smads to modulate their activity, (2) interacting with and modulating the activity of other signaling proteins (e.g., kinases), and (3) directly interacting with or phosphorylating TGF-β receptors, initiating parallel signaling pathways. The authors discuss the evidence for these mechanisms and their implications for understanding the complexity of TGF-β signaling. They also explore the involvement of non-Smad signaling in apoptosis, epithelial-mesenchymal transition, cell proliferation, matrix regulation, and cell differentiation. The article emphasizes the importance of non-Smad signaling in modulating Smad activity and integrating with Smad signaling to regulate various cellular processes.The article reviews the role of non-Smad signaling proteins in TGF-β signaling pathways. It highlights three general mechanisms by which non-Smad proteins contribute to physiological responses to TGF-β: (1) directly modifying Smads to modulate their activity, (2) interacting with and modulating the activity of other signaling proteins (e.g., kinases), and (3) directly interacting with or phosphorylating TGF-β receptors, initiating parallel signaling pathways. The authors discuss the evidence for these mechanisms and their implications for understanding the complexity of TGF-β signaling. They also explore the involvement of non-Smad signaling in apoptosis, epithelial-mesenchymal transition, cell proliferation, matrix regulation, and cell differentiation. The article emphasizes the importance of non-Smad signaling in modulating Smad activity and integrating with Smad signaling to regulate various cellular processes.