The article reviews the non-Smad pathways in TGF-β signaling, which are activated by ligand-occupied receptors to modulate downstream cellular responses. These pathways include MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. The review focuses on recent advances in understanding the molecular and biochemical mechanisms of these non-Smad pathways and their functions. Key non-Smad pathways discussed include the Erk, JNK/p38, and PI3K/Akt pathways. Erk activation is crucial for epithelial to mesenchymal transition (EMT) and is regulated by Shc and Grb2. JNK and p38 MAPK activation is independent of Smads and involves TRAF6 and TAK1. RhoA activation is also independent of Smads and plays a role in EMT by controlling actin cytoskeleton organization. The PI3K/Akt pathway contributes to EMT through mTOR activation and antagonizes Smad-mediated responses. The review highlights the importance of these non-Smad pathways in mediating diverse biological responses to TGF-β and their potential as therapeutic targets.The article reviews the non-Smad pathways in TGF-β signaling, which are activated by ligand-occupied receptors to modulate downstream cellular responses. These pathways include MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. The review focuses on recent advances in understanding the molecular and biochemical mechanisms of these non-Smad pathways and their functions. Key non-Smad pathways discussed include the Erk, JNK/p38, and PI3K/Akt pathways. Erk activation is crucial for epithelial to mesenchymal transition (EMT) and is regulated by Shc and Grb2. JNK and p38 MAPK activation is independent of Smads and involves TRAF6 and TAK1. RhoA activation is also independent of Smads and plays a role in EMT by controlling actin cytoskeleton organization. The PI3K/Akt pathway contributes to EMT through mTOR activation and antagonizes Smad-mediated responses. The review highlights the importance of these non-Smad pathways in mediating diverse biological responses to TGF-β and their potential as therapeutic targets.