Transforming growth factor beta (TGF-beta) is a multifunctional factor that induces a wide variety of cellular processes which affect growth and differentiation. TGF-beta exerts its effects through a heteromeric complex between two transmembrane serine/threonine kinase receptors, the type I and type II receptors. However, the intracellular signaling pathways through which TGF-beta receptors act to generate cellular responses remain largely undefined. Here, we report that TGF-beta initiates a signaling cascade leading to stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) activation. Expression of dominant-interfering forms of various components of the SAPK/JNK signaling pathways including Rho-like GTPases, mitogen-activated protein kinase (MAPK) kinase kinase 1 (MEKK1), MAPK kinase 4 (MKK4), SAPK/JNK, and c-Jun abolishes TGF-beta-mediated signaling. Therefore, the SAPK/JNK activation contributes to TGF-beta signaling.