The first week of human pre-embryo development is characterized by the induction of totipotency and then pluripotency. The understanding of this delicate process will have far reaching implication for in vitro fertilization and regenerative medicine. Human mature MII oocytes and embryonic stem (ES) cells are both able to achieve the feat of cell reprogramming towards pluripotency, either by somatic cell nuclear transfer or by cell fusion, respectively. Comparison of the transcriptome of these two cell types may highlight genes that are involved in pluripotency initiation. Therefore, based on a microarray compendium of 205 samples, produced in our laboratory or from public databases, we compared the gene expression profile of mature MII oocytes and human ES cells (hESC) to that of somatic tissues. We identified a common oocyte/hESC gene expression profile, which included a strong cell cycle signature, a large chromatin remodelling network (TOP2A, DNMT3B, JARID2, SMARCA5, CBX1, CBX5) and 18 different zinc finger transcription factors, including ZNF84. Strikingly, a large set of genes was found to code for proteins involved in the ubiquitination and proteasome pathway. Upon hESC differentiation into embryoid bodies, the transcription of this pathway declines. In vitro, we observed a selective sensitivity of hESC to the inhibition of the activity of the proteasome, resulting in loss of pluripotency and cell growth at doses without any detectable effects on differentiated cells. Taken together, these results suggest that the proteasome pathway may play a role in initiating and maintaining pluripotency during early development and in hESC.