Pluripotency, the ability to give rise to all the cell lineages of the body, is a hallmark of embryonic stem cells (ESCs), and understanding its regulation is essential for effectively controlling ESC differentiation. Ludovic Vallier, Roger Pedersen and colleagues now demonstrate a role for Nanog - a crucial component of the pluripotency transcriptional network - in safeguarding human ESCs (hESCs) against the differentiation-inducing effects of extracellular signals (p. 1339). They show that Activin/Nodal signalling, which maintains hESC pluripotency through SMAD2/3 activation, maintains NANOG expression through the binding of SMAD2/3 to the NANOG promoter, which blocks the differentiation of pluripotent cells into neuroectoderm. Conversely, NANOG appears to limit the Activin/Nodal-induced transcriptional activity of SMAD2/3 by forming a protein complex with it. This interaction prevents the differentiation of pluripotent cells from mesendoderm into endoderm, which is otherwise induced by exposure to BMP4 and Activin/Nodal signalling. From their findings, the researchers propose that a negative-feedback loop involving Nanog and Smad2/3 safeguards pluripotent cells against differentiation.