Long non-coding RNAs (lncRNAs) play significant roles in cancer by influencing chromatin remodeling, transcriptional regulation, and post-transcriptional processes. They function as decoys, scaffolds, and enhancer RNAs, and are involved in various mechanisms such as chromatin interactions, competing endogenous RNAs (ceRNAs), and natural antisense transcripts (NATs). This review summarizes the characteristics, functions, and mechanisms of lncRNAs, discusses methods for identifying and annotating them, and explores future opportunities for lncRNA-based therapies using antisense oligonucleotides (ASOs). LncRNAs are defined as RNA molecules longer than 200 nucleotides and are present in large numbers in the genome. They typically lack functional open reading frames (ORFs) but can have both protein-coding and non-coding functions. Many lncRNAs are lowly expressed and are found in various tissues, with the brain and central nervous system showing the highest diversity of expressed lncRNAs. LncRNAs can be located in the cytoplasm and nucleus and have varying stability, with some being highly stable. LncRNAs regulate transcription through various mechanisms, including chromatin remodeling, chromatin interactions, and ceRNA functions. For example, KCNQ1OT1 acts as a signal lncRNA by recruiting histone methyltransferases and polycomb repressive complex 2 (PRC2), leading to gene silencing. ANRIL/CDKN2B functions as a scaffold to mediate transcriptional silencing of the INK4b-ARF-INK4a locus. HOTAIR works with PRC2 to mediate repression of the homeobox D cluster (HOXD) locus. LncRNAs also play a role in chromatin looping through enhancer RNAs (eRNAs), which facilitate chromatin interactions. Studies have shown that eRNAs are involved in gene expression regulation and chromatin looping. Additionally, lncRNAs can act as NATs, influencing the expression of their sense transcripts. For example, Wrap53, a NAT, can induce TP53 expression and is overexpressed in cancer cells. LncRNAs can also function as ceRNAs by competing with microRNAs for binding sites, thereby modulating gene expression. For instance, HULC is highly upregulated in hepatocellular carcinoma and can reduce miR-372 expression, leading to increased expression of its target transcript PRKACB. The review also discusses approaches for identifying and annotating lncRNAs, including RNA-seq, microarray-based methods, and sequencing technologies such as PacBio. These methods help in understanding the structure and function of lncRNAs. Additionally, ASOs are used to modulate lncRNA expression, offering a promising tool for therapeutic applications. In conclusion, lncRNLong non-coding RNAs (lncRNAs) play significant roles in cancer by influencing chromatin remodeling, transcriptional regulation, and post-transcriptional processes. They function as decoys, scaffolds, and enhancer RNAs, and are involved in various mechanisms such as chromatin interactions, competing endogenous RNAs (ceRNAs), and natural antisense transcripts (NATs). This review summarizes the characteristics, functions, and mechanisms of lncRNAs, discusses methods for identifying and annotating them, and explores future opportunities for lncRNA-based therapies using antisense oligonucleotides (ASOs). LncRNAs are defined as RNA molecules longer than 200 nucleotides and are present in large numbers in the genome. They typically lack functional open reading frames (ORFs) but can have both protein-coding and non-coding functions. Many lncRNAs are lowly expressed and are found in various tissues, with the brain and central nervous system showing the highest diversity of expressed lncRNAs. LncRNAs can be located in the cytoplasm and nucleus and have varying stability, with some being highly stable. LncRNAs regulate transcription through various mechanisms, including chromatin remodeling, chromatin interactions, and ceRNA functions. For example, KCNQ1OT1 acts as a signal lncRNA by recruiting histone methyltransferases and polycomb repressive complex 2 (PRC2), leading to gene silencing. ANRIL/CDKN2B functions as a scaffold to mediate transcriptional silencing of the INK4b-ARF-INK4a locus. HOTAIR works with PRC2 to mediate repression of the homeobox D cluster (HOXD) locus. LncRNAs also play a role in chromatin looping through enhancer RNAs (eRNAs), which facilitate chromatin interactions. Studies have shown that eRNAs are involved in gene expression regulation and chromatin looping. Additionally, lncRNAs can act as NATs, influencing the expression of their sense transcripts. For example, Wrap53, a NAT, can induce TP53 expression and is overexpressed in cancer cells. LncRNAs can also function as ceRNAs by competing with microRNAs for binding sites, thereby modulating gene expression. For instance, HULC is highly upregulated in hepatocellular carcinoma and can reduce miR-372 expression, leading to increased expression of its target transcript PRKACB. The review also discusses approaches for identifying and annotating lncRNAs, including RNA-seq, microarray-based methods, and sequencing technologies such as PacBio. These methods help in understanding the structure and function of lncRNAs. Additionally, ASOs are used to modulate lncRNA expression, offering a promising tool for therapeutic applications. In conclusion, lncRN