Cancer stemness is proposed to be the main cause of metastasis and tumor relapse after conventional therapy due to the main properties of cancer stem cells. These include unlimited self-renewal, the low percentage in a cell population, asymmetric/symmetric cell division, and the hypothetical different nature for absorbing external substances. As the mechanism of how cancer stemness is maintained remains unknown, further investigation into the basic features of cancer stemness is required. Many articles demonstrated that glucose-regulated protein 78 (GRP78) plays a key role in cancer stemness, suggesting that this molecule is feasible for targeting cancer stem cells. This review summarizes the history of finding cancer stem cells, as well as the functions of GRP78 in cancer stemness, for discussing the possibility of targeting GRP78 to eradicate cancer stemness.