Cancer stem cells (CSCs) are a small subpopulation of tumor cells critical for tumor development. Their unique abilities, such as self-renewal, have resulted in tumor resistance to various cancer treatments, including traditional chemotherapy and latest immunotherapy. CSCs-targeting therapy is a promising treatment to overcome the therapeutic resistances to different tumors. However, despite their significance, the regulatory mechanism generating therapy-resistant CSCs is still obscure. Long non-coding RNAs (lncRNAs) are key regulators in various biological processes, including cell proliferation, apoptosis, migration, and invasion. Recent studies have revealed that lncRNAs play an important role in the therapeutic resistance of CSCs. Here we summarize the latest studies on the regulatory role of lncRNAs in sustaining the stemness of CSCs, and discuss the associated mechanisms behind these behavior changes in CSCs-related chemo- and immune-resistance. Future research implications are also discussed, shedding light on the potential CSCs-targeted strategies to break through the resistance of current therapies. Copyright © 2020. Published by Elsevier B.V.