Many members of transforming growth factor-beta (TGF-beta) superfamily, including not only TGF-beta, but also the activins, and bone morphogenetic proteins (BMPs), have been demonstrated to affect the development and function of immune cells. From the proliferation and differentiation of pluripotent stem cells, to the activation and migration of mature lymphoid and myeloid lineages, the TGF-betas have been recognized for their ability to modulate the manner in which such cells respond to stimuli in their environment. Recent studies involving disruption of this pathway in genetically engineered mice now emphasize the importance of this activity and validate functional models predicted by in vitro studies. Phenotypic differences between mice harboring mutations in the TGF-beta1 ligand and the TGF-beta receptor-activated signaling intermediate Smad3 are presented and serve to highlight the valuable role of these in vivo genetic tests of function.