The biology of embryonic stem (ES) cell lines has opened new avenues both in the biology of pathophysiological development and in potential regenerative medicine. The transforming growth factor (TGF)-beta superfamily plays a major role in the development of organisms. The family comprises a variety of growth factors that feature disparate functions in the biology of ES cells. These factors regulate both stemness and various cell differentiation pathways. Despite intensive work, the role of this family of growth factors in the function of ES cells is still unclear. More specifically, mouse and human ES cells differentially respond to these factors. Inspired by the biology of development, this review summarizes the current knowledge on the pleiotropic effects of these growth factors on the fate of ES cells.