Although normal stem cells and CSCs share key signaling pathways and transcription factors which regulate self-renewal and determine cell fate (Wnt/β-catenin, BMPs, Sonic hedgehog (SHH), Notch, Sox2, Oct4, Nanog, Bmi-1, PI3K/Akt cascade), in normal stem cells this signaling tightly depends on extrinsic growth factor signals, while in CSCs, dysregulation or hyperactivation of transcription factor-mediated pathways drives abnormal self-renewal and tumorigenesis, sustaining differentiation into highly proliferative cancer cells (10). The gene discussed is POU5F1; the disease is cancer.