To rejuvenate tissues and/or repair wounds, stem cells must receive extrinsic signals from their surrounding environment and integrate them with their intrinsic abilities to self-renew and differentiate to make tissues. Increasing evidence suggests that the superfamily of transforming growth factor-βs (TGF-βs) constitute integral components in the intercellular crosstalk between stem cells and their microenvironment. In this review, we summarize recent advances in our understanding of TGF-β superfamily functions in embryonic and adult stem cells. We discuss how these pathways help to define the physiological environment where stem cells reside, and how perturbations in the signaling circuitry contribute to cancers.