A dual role of transforming growth factor β (TGF-β), to both suppress and promote tumor progression and metastasis, has been well established, but its molecular basis has remained elusive. In this review, we focus on Smad proteins, which are central mediators of the signal transduction of TGF-β family members. We describe current knowledge of cell-type-specific binding patterns of Smad proteins and mechanisms of transcriptional regulation, obtained from recent studies on genome-wide binding sites of Smad molecules. We also discuss potential application of the genome-wide analyses for cancer research, which will allow clarification of the complex mechanisms occurring during cancer progression, and the identification of potential biomarkers for future cancer diagnosis, prognosis and therapy.