Transforming growth factor-bs (TGF-bs) regulate pivotal cellular processes such as proliferation, differentiation and apoptosis. Following receptor-induced activation, heteromeric Smad complexes translocate into the nucleus, where they act as transcription factors. Many different cell surface receptors and intracellular proteins influence the TGF-b pathway, demonstrating that signal transduction does not proceed in a linear fashion but rather through a complex network of cascades that mutually influence each other. The intracellular signaling events mediating the effects of TGF-b are multiple, involving extensive cross-talk between Smad-dependent and MAP-kinase-dependent pathways. In addition, the Smads regulate transcription through functional cooperativity and physical interactions with other transcription factors. We are only beginning to understand the importance of the balance between these cascades as a determinant of the response to TGF-b, and have yet to determine the roles that alterations in these pathways might play in cancer. It is logical to predict that any functional impairment in the TGF-b pathway may predispose to cancer. I will discuss the molecular mechanisms of inactivation of TGF-b signaling during carcinogenesis.