The stem cell field witnessed a genuine breakthrough when a combination of solely four transcription factors (Oct3/4, Sox2, Klf4 and c-Myc) proved enough to revert, in vitro, the differentiated status of a variety of cell types back to pluripotency, giving rise to so-called induced pluripotent stem (iPS) cells. Ten years after this revolutionary discovery, the attempts to induce pluripotency have not been limited to the culture dish. Some studies have interrogated the downstream effects of the overexpression of OSKM reprogramming factors in the living organism. In this Chapter, we dissect the proof-of-principle studies that demonstrated that cellular reprogramming to pluripotency can be induced in vivo, in spite of unfavorable pro-differentiation signals present within the tissues. The links of in vivo reprogramming to pluripotency with tumorigenesis and teratoma formation, and the cross-talk with cellular senesce and tissue injury are also discussed.