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Pluripotent cells have unique properties of self-renewal while maintaining develop-mental potential to differentiate into all three germ layers. By definition, pluripo-tent cells have no predetermined lineage program, thereby forming the funda-mental basis of enquiry and experimen-tal investigations to understand cell fate decisions. Molecular and cellular insights into human pluripotent stem cell (hPSC) fate hold the potential to impact a broad range of human disease for cell replace-ment therapies and disease modeling and therefore are highly prioritized in current research efforts. The majority of concepts regarding ground state pluripotency have been derived from large-scale genomic,1 epigenomic2 and proteomic3 experimen-tation using a variety of hPSC lines cul-tured and derived from very divergent culture and derivation methods. In turn, these global analyses are unique to the human and differ from sources used for the study of mouse ESCs or iPSCs, which are derived from inbreed strains and stan-dardized culture conditions. Although this provides consistent results using mouse PSCs, the surrogacy that can be translated to hPSCs to improve differen-tiation toward applications is completely unclear. Nevertheless, commonality in pluripotent state emerges from a core set of transcription factors, including Oct4, Sox2 and Nanog.4 Unique to hPSCs, these factors regulate pluripotency by associat-ing with epigenetic (e.g., Polycomb and Trithorax) regulators to establish bivalent marks.5 However, the complex interplay among transcription factors, cell signal-ing and bivalent epigenetic marks has not yet been fully described in the context of hPSC differentiation. Human pluripotency A difficult state to make smart choices shravanti rampalli and Mickie Bhatia