Human cancers emerge from cancer stem cells (CSCs), which are resistant to cancer chemotherapeutic agents, radiation, and cell death. Moreover, autophagy provides the cytoprotective effect which contributes to drug resistance in these cells. Furthermore, much evidence shows that CSCs cause tumor initiation, progression, metastasis, and cancer recurrence. Various signaling pathways including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), maternal embryonic leucine zipper kinase (MELK), NOTCH1, and Wnt/β-catenin as well as the CSC markers maintain CSC properties. Several mechanisms including overexpression of ABC multidrug resistance transporters, a deficiency in mitochondrial-mediated apoptosis, upregulation of c-FLIP, overexpression of anti-apoptotic Bcl-2 family members and inhibitors of apoptosis proteins (IAPs), and PI3K/AKT signaling contribute to enhancing resistance to chemotherapeutic drugs and cell death induction in CSCs in various cancers. Studying such pathways may help provide detailed understanding of CSC mechanisms of resistance to chemotherapeutic agents and apoptosis and may lead to the development of effective therapeutics to eradicate CSCs.