Smads are intracellular signalling mediators for the family of transforming growth factor beta (TGF-beta)-related growth and differentiation factors, which signal through transmembrane serine/threonine kinases. Following receptor-induced activation, heteromeric Smad complexes translocate into the nucleus, where they act as transcription factors. Recent progress has revealed that Smad signalling is not merely determined by activation of the class of TGF-beta receptors, but is also regulated through crosstalk with other kinase signalling cascades. In addition, the Smads regulate transcription through functional cooperativity and physical interactions with other transcription factors, which might also be targets for regulation by other signalling cascades. This signalling crosstalk might explain the complexity of the responses to TGF-beta and related factors.