The mechanism of mammalian gene regulation is highly complex, involving multiple layers of feedback control loops and dynamic chromatin remodeling. The current approach used to dissect the genetic circuitry of mammalian gene regulation utilizes somatic cells and protein fusion as a means to modulate protein interactions. This approach has several limitations that include (i) genome inaccessibility, (ii) high background interferences and, (iii) limited cellular phenotypes. Previously, the two broad fields of research "control of gene expression" and "stem cell biology" had been pursued separately by cell biologists; this review outlines evidence suggesting that integration of these two fields would provide a comprehensive platform for interdisciplinary research seeking to address mechanistic questions concerning gene regulation-that could have enormous implication for the development of therapeutic applications.