There is growing evidence that regions of the genome that cannot encode proteins play an important role in diseases. These regions are usually transcribed into long non-coding RNAs (lncRNAs). LncRNAs, little or no coding potential, are defined as capped transcripts longer than 200 nucleotides. New sequencing technologies have shown that a large number of aberrantly expressed lncRNAs are associated with multiple cancer types and indicated they have emerged as an important class of pervasive genes during the development and progression of cancer. However, the underlying mechanism in cancer is still unknown. Therefore, it is necessary to elucidate the lncRNA function. Notably, many lncRNAs dysregulation are associated with Oral squamous cell carcinoma (OSCC) and affect various aspects of cellular homeostasis, including proliferation, survival, migration or genomic stability. This review expounds the up- or down-regulation of lncRNAs in OSCC and the molecular mechanisms by which lncRNAs perform their function in the malignant cell. Finally, the potential of lncRNAs as non-invasive biomarkers for OSCC diagnosis are also described. LncRNAs hold promise as prospective novel therapeutic targets, but more research is needed to gain a better understanding of their biologic function.

Oral squamous cell carcinoma (OSCC), the eighth most prevalent cancer in the world, arises from the interaction of multiple factors including tobacco, alcohol consumption, and betel quid. Chemotherapeutic agents such as cisplatin, 5‐fluorouracil, and paclitaxel have now become the first‐line options for OSCC patients. Nevertheless, most OSCC patients eventually acquire drug resistance, leading to poor prognosis. With the discovery and identification of non‐coding RNAs (ncRNAs), the functions of dysregulated ncRNAs in OSCC development and drug resistance are gradually being widely recognized. The mechanisms of drug resistance of OSCC are intricate and involve drug efflux, epithelial‐mesenchymal transition, DNA damage repair, and autophagy. At present, strategies to explore the reversal of drug resistance of OSCC need to be urgently developed. Nano‐delivery and self‐cellular drug delivery platforms are considered as effective strategies to overcome drug resistance due to their tumor targeting, controlled release, and consistent pharmacokinetic profiles. In particular, the combined application of new technologies (including CRISPR systems) opened up new horizons for the treatment of drug resistance of OSCC. Hence, this review explored emerging regulatory functions of ncRNAs in drug resistance of OSCC, elucidated multiple ncRNA‐meditated mechanisms of drug resistance of OSCC, and discussed the potential value of drug delivery platforms using nanoparticles and self‐cells as carriers in drug resistance of OSCC.