Long non-coding RNAs (lncRNAs) play crucial roles in gene transcription regulation, with diverse mechanisms and disease relevance. This review discusses how lncRNAs function in cis and trans to regulate gene expression, often through interactions with transcription factors, chromatin remodeling, and 3D genome organization. Key lncRNAs such as XIST regulate X-chromosome inactivation, while others like HASTER and FENDRR act as transcription stabilizers, fine-tuning the expression of dosage-sensitive transcription factors. Some lncRNAs, such as lincRNA-p21 and Maenli, activate gene transcription locally, while others influence gene expression in trans. The review highlights the importance of lncRNAs in human diseases and their potential as therapeutic targets. Mechanisms include cis-activation through transcription initiation, transcript elongation, and processing, as well as trans-regulation via nuclear assemblies and triplex formation. LncRNAs also contribute to allele-specific repression, particularly in imprinted loci. The study of lncRNAs provides insights into non-coding genome variation and its impact on human diseases.Long non-coding RNAs (lncRNAs) play crucial roles in gene transcription regulation, with diverse mechanisms and disease relevance. This review discusses how lncRNAs function in cis and trans to regulate gene expression, often through interactions with transcription factors, chromatin remodeling, and 3D genome organization. Key lncRNAs such as XIST regulate X-chromosome inactivation, while others like HASTER and FENDRR act as transcription stabilizers, fine-tuning the expression of dosage-sensitive transcription factors. Some lncRNAs, such as lincRNA-p21 and Maenli, activate gene transcription locally, while others influence gene expression in trans. The review highlights the importance of lncRNAs in human diseases and their potential as therapeutic targets. Mechanisms include cis-activation through transcription initiation, transcript elongation, and processing, as well as trans-regulation via nuclear assemblies and triplex formation. LncRNAs also contribute to allele-specific repression, particularly in imprinted loci. The study of lncRNAs provides insights into non-coding genome variation and its impact on human diseases.