This review discusses the emerging roles of long non-coding RNAs (lncRNAs) in controlling gene transcription. LncRNAs, defined as transcripts longer than 500 nucleotides that do not encode proteins, have been shown to have essential cis-regulatory functions that cannot be easily achieved by DNA-binding transcription factors. Some lncRNAs, such as *XIST* and imprinted lncRNAs, control X-chromosome inactivation and allele-specific repression, respectively. Other lncRNAs, like *CHASERR*, *PVT1*, and *HASTER*, act as transcription-stabilizing elements that fine-tune the activity of dosage-sensitive genes encoding transcription factors. Genetic studies have revealed that defects in these transcription stabilizers often lead to severe phenotypes. LncRNAs can also contribute to local activation of gene transcription, as seen in the case of *lncRNA-p21* and *Maenli*. Additionally, some lncRNAs influence gene transcription in trans, such as *HOTAIR*, which regulates distant HOXD locus genes through PRC2 targeting. The review highlights the importance of lncRNA-containing nuclear assemblies, such as nuclear speckles and paraspeckles, in global transcription control and RNA processing. It also discusses the role of lncRNAs in forming triplex structures to target distant genomic sites for regulation. The review further explores the involvement of lncRNAs in human diseases, including Mendelian and polygenic disorders, and their potential as therapeutic targets. The understanding of lncRNA functions is helping to unravel the impact of non-coding genome variation and could lead to novel therapeutic strategies.This review discusses the emerging roles of long non-coding RNAs (lncRNAs) in controlling gene transcription. LncRNAs, defined as transcripts longer than 500 nucleotides that do not encode proteins, have been shown to have essential cis-regulatory functions that cannot be easily achieved by DNA-binding transcription factors. Some lncRNAs, such as *XIST* and imprinted lncRNAs, control X-chromosome inactivation and allele-specific repression, respectively. Other lncRNAs, like *CHASERR*, *PVT1*, and *HASTER*, act as transcription-stabilizing elements that fine-tune the activity of dosage-sensitive genes encoding transcription factors. Genetic studies have revealed that defects in these transcription stabilizers often lead to severe phenotypes. LncRNAs can also contribute to local activation of gene transcription, as seen in the case of *lncRNA-p21* and *Maenli*. Additionally, some lncRNAs influence gene transcription in trans, such as *HOTAIR*, which regulates distant HOXD locus genes through PRC2 targeting. The review highlights the importance of lncRNA-containing nuclear assemblies, such as nuclear speckles and paraspeckles, in global transcription control and RNA processing. It also discusses the role of lncRNAs in forming triplex structures to target distant genomic sites for regulation. The review further explores the involvement of lncRNAs in human diseases, including Mendelian and polygenic disorders, and their potential as therapeutic targets. The understanding of lncRNA functions is helping to unravel the impact of non-coding genome variation and could lead to novel therapeutic strategies.