Cancer stem cells (CSCs) are rare subpopulations within tumors which are recognized as culprits in cancerrecurrence, drug resistance and metastasis. However, the molecular mechanisms of how CSCs are regulatedremain elusive. Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcriptionfactors with diverse functions in cell differentiation, proliferation, embryogenesis and pluripotency. Recentprogress has highlighted the significance of KLFs, especially KLF4, in cancer and CSCs. Therefore, for bettertherapeutics of cancer disease, it is crucial to develop a deeper understanding of the mechanisms of how KLF4regulate CSC functions. Herein we summarized the current understanding of the transcriptional regulation ofK LF4 in CSCs, and discussed the functional implications of targeting CSCs for potential cancer therapeutics.