Tissue-specific alternate splicing is an important means of regulating gene expression during development. The effector proteins for the transforming growth factor-beta signaling pathway, the SMADs, encode distinct isoforms generated via alternate splicing, which appear to have distinct tissue-specific expression profiles and functions. Here, we discuss the roles of various SMAD isoforms, and the consequences of mis-regulation of SMAD splicing in development and tissue homeostasis.