Abstract Pluripotent stem cells can give rise to all cell types in the body and have therefore enormous potential for regenerative medicine, and provide a powerful tool for studies in developmental biology and pharmacology. Advances in transforming somatic cells directly into pluripotent (induced pluripotent stem: iPS) cells provide an attractive avenue for generating large numbers of customized stem cells. Notable progress has been made to efficiently generate iPS cells, including integration-free lines, however, detailed mechanistic insights regarding the establishment, subsequent maintenance and efficient exit from pluripotency are still lacking. Over the past four years our program project team has made significant contributions towards a better understanding of these (Smith et al. Nature 2012,14; Ziller et al. Nature 2013,14; Gifford et al. Cell 2013; Tsankov et al. Nature 2015; Liao et al. Nature Genetics 2015; Cacchiarelli et al Cell in 2015 and more). As would be expected the results have helped pinpoint areas that need further experimentation and also presented us with a new set of lingering questions that are central to our understanding of human pluripotency. Our aims in the framework of the larger program project (past and future) will provide crucial insights towards this end and as a result will have a broad impact on the fields of human reprogramming and pluripotency. Over the next years, we will apply a complex, recently engineered DNMT1 knockout/inducible rescue human ES cell line to address fundamental questions in human stem cell biology with a focus on the naïve versus primed states. We will apply the latest advances in single cell technology and analysis to gain unprecedented insights into the biology of human pluripotency. Lastly, we will use our recently developed and characterized human secondary reprogramming system to define and study one of the most critical points (the final transition) in the reprogramming process that is also the least understood.