The promyelocytic leukemia (PML) protein, initially discovered as a part of the PML/retinoic acid receptor alpha fusion protein, has been found to be a critical player in oncogenesis and tumor progression. Multiple cellular activities, including DNA repair, alternative lengthening of telomeres, transcriptional control, apoptosis and senescence, are regulated by PML and its featured subcellular structure, the PML nuclear body. In correspondence with its role in many important life processes, PML mediates several complex downstream signaling pathways. The determinant function of PML in tumorigenesis and cancer progression raises the interest in its involvement in cancer stem cells (CSCs), a subpopulation of cancer cells that share properties with stem cells and are critical for tumor propagation. Recently, there are exciting discoveries concerning the requirement of PML in CSC maintenance. Growing evidences strongly suggest a positive role of PML in regulating CSCs in both hematopoietic cancers and solid tumors, whereas the underlying mechanisms may be different and remain elusive. Here we summarize and discuss the PML-mediated signaling pathways in cancers and their potential roles in regulating CSCs.