Transforming growth factor-beta (TGF-beta) and related cytokines control the development and homeostasis of many tissues by regulating the expression of genes that determine cell phenotype. Recent progress has elucidated the way in which members of the TGF-beta family initiate their signal through transmembrane receptors and transmit it to target genes via the Smad family of signal-transducing proteins. This review describes TGF-beta signaling pathways as currently understood and mutations of the genes that encode Smads that disrupt the function of these proteins and cause various forms of cancer.