The self-renewal of pluripotent embryonic stem (ES) cells is mediated by the activation of the STAT3 transcription factor. This study demonstrates that STAT3 plays a central role in maintaining the pluripotential stem cell phenotype, contrasting with its role in inducing differentiation in somatic cells. The research shows that the activation of STAT3 is essential for ES cell self-renewal, and its inhibition leads to differentiation. The study used chimeric receptors and dominant interfering mutants to investigate the role of STAT3 in ES cell signaling. It was found that the four STAT3 docking sites in gp130 are not functionally equivalent, and mutations in these sites affect self-renewal. The study also generated an inducible STAT3F transgene, which blocks self-renewal and promotes differentiation when expressed in ES cells. These findings highlight the importance of STAT3 in ES cell self-renewal and suggest that cell-specific interpretation of STAT3 activation is crucial for understanding the diverse developmental effects of LIF family cytokines. The study provides a molecular model for stem cell regulation in mammals and has implications for the extension of ES cell technology to non-mouse species.The self-renewal of pluripotent embryonic stem (ES) cells is mediated by the activation of the STAT3 transcription factor. This study demonstrates that STAT3 plays a central role in maintaining the pluripotential stem cell phenotype, contrasting with its role in inducing differentiation in somatic cells. The research shows that the activation of STAT3 is essential for ES cell self-renewal, and its inhibition leads to differentiation. The study used chimeric receptors and dominant interfering mutants to investigate the role of STAT3 in ES cell signaling. It was found that the four STAT3 docking sites in gp130 are not functionally equivalent, and mutations in these sites affect self-renewal. The study also generated an inducible STAT3F transgene, which blocks self-renewal and promotes differentiation when expressed in ES cells. These findings highlight the importance of STAT3 in ES cell self-renewal and suggest that cell-specific interpretation of STAT3 activation is crucial for understanding the diverse developmental effects of LIF family cytokines. The study provides a molecular model for stem cell regulation in mammals and has implications for the extension of ES cell technology to non-mouse species.