The maintenance of pluripotency relies on an intricate transcriptional network hinged on a key set of transcription factors. Pluripotent stem cells have been shown to be sensitive to modulations of the cellular abundance and transcriptional activity of these key pluripotency factors. Recent evidence highlights the important role of post-translational modifications, including ubiquitination, sumoylation, phosphorylation, methylation, and acetylation, in regulating the levels and activity of pluripotency factors to achieve a balance between pluripotency and differentiation.