Primordial germ cells (PGCs) give rise to gametes, which transmit genetic and epigenetic information to succeeding generations. Human PGCs (hPGCs) undergo extensive epigenetic rewiring, which entails genome-wide DNA demethylation and acute histone remodeling, shaping conserved regulatory networks for gametogenesis and embryonic development. However, the mechanisms orchestrating epigenetic programming remain largely uncharacterized in hPGCs. Recent studies suggest that the histone variant H3.3 may replace canonical histone H3 within nucleosomes to reset the histone modification landscape and counteract DNA methylation. My research investigates whether H3.3 mediates the epigenetic reprogramming of hPGCs. I employ in vitro models that recapitulate hPGC development, using human induced pluripotent stem cells (hiPSCs) to derive precursors of mesendoderm (pre-ME) and differentiate them into hPGC-like cells (hPGCLCs) resembling early hPGCs. My results show that H3.3 is downregulated upon exit from pluripotency in pre-ME, later enriched in hPGCLCs concomitant with increased H3K4me3 levels, previously associated with H3.3 deposition. Additionally, premature H3.3 overexpression in pre-ME impairs hPGCLC specification, indicating its dynamic expression is required for hPGCLC differentiation and may mediate reprogramming. To test this, I am implementing a new approach involving the co-culture of hPGCLCs with mouse embryonic somatic cells, reconstituting the physiological niche of PGCs, allowing further development and epigenetic resetting. I am using this method along with hiPSC lines generated for inducible H3.3 repression and overexpression in order to investigate the role of H3.3 in this vital process. Ultimately, this study aims to broaden our understanding of PGC reprogramming, unraveling the rationale behind these intricate epigenetic changes.