Embryonic stem cells (ESCs) are derived from the inner cell mass of the blastocysts and are characterized by the ability to renew themselves (self-renewal) and the capability to generate all the cells within the human body. In contrast, inducible pluripotent stem cells (iPSCs) are generated by transfection of four transcription factors in somatic cells. Like embryonic stem cells, they are able to self-renew and differentiate. Because of these features, both ESCs and iPSCs, are under intense clinical investigation for cell-based therapy. In this review, we revisit stem cell biology and add a new layer of complexity. In particular, we will highlight some of the complexities of the system, but also where there may be therapeutic potential for modulation of intrinsic stem cells and where particular caution may be needed in terms of cell transplantation therapies.