The property of pluripotency confers the capacity for differentiation into a large number of cell types including extra-embryonic, somatic and germinal cells. During normal development, pluripotency is acquired by the cells of the early embryo, which shortly thereafter undergo differentiation, whereas embryonic stem cells (ESCs) uniquely maintain pluripotency while undergoing extensive in vitro proliferation. Studies using ESCs have begun to unravel the network of cytokines and transcription factors responsible for their maintenance of pluripotency. Surprisingly, mouse and human ESCs display significant differences in such mechanisms despite their similar embryonic origins. In this review, we compare the properties of pluripotent embryonic cells with those of ESCs to establish a general model for the mechanisms maintaining pluripotency. We first consider whether mouse and human ESCs represent comparable stages of early embryonic development. We then describe how human embryoid body (EB) differentiation could be used as a model of embryonic development. Finally, to concretely illustrate the discussion, we discuss our recent results concerning Nodal function in controlling cell fate at early stages of human EB development. With the new perspective of these findings, we suggest a previously unrecognized role of TGF-beta pathway signaling in maintaining pluripotency at early stages of mammalian embryonic development.