Cancer metastasis, defined by the epithelial to mesenchymal transition (EMT) of tumor cells, disseminates from the primary site to progressively colonize in distant tissues, and accounts for most cancer-associated deaths. However, studies on the molecular basis of cancer metastasis are still in their infancy. Besides genetic mutations, accumulating evidence indicates that epigenetic alterations also contribute in a major way to the refractory nature of cancer metastasis. Considered as one of the essential epigenetic regulators, long non-coding RNAs (lncRNAs) can act as signaling regulators, decoys, guides and scaffolds, modulating key molecules in every step of cancer metastasis including dissemination of carcinoma cells, intravascular transit, and metastatic colonization. Although still having limited clinical application, it is encouraging to witness that several lncRNAs, including CCAT1 and HOTAIR, are under clinical evaluation as potential biomarkers for cancer staging and assessment of metastatic potential. In this review, we focus on the molecular mechanisms underlying lncRNAs in the regulation of cancer metastasis and discuss their clinical potential as novel therapeutic targets as well as their diagnostic and prognostic significance for cancer treatment. Gaining clear insights into the detailed molecular basis underlying lncRNA-modulated cancer metastasis may provide previously unrecognized diagnostic and therapeutic strategies for metastatic patients. Copyright © 2021 Elsevier B.V. All rights reserved.