Xist is a long non-coding RNA (lncRNA) that plays a critical role in X-chromosome inactivation (XCI), a process that silences one of the two X chromosomes in female mammals. This study reveals that Xist spreads across the X-chromosome by exploiting three-dimensional (3D) genome architecture. During XCI initiation, Xist initially localizes to distal regions of the X-chromosome that are not defined by specific sequences but by their spatial proximity to the Xist transcription locus. Xist then spreads across the chromosome by modifying chromatin structure and accessing newly accessible regions. The silencing domain of Xist is essential for spreading across actively transcribed regions and accessing the entire chromosome. The study also shows that Xist localizes to the periphery of actively transcribed regions and gradually spreads into them through the A-repeat domain. Xist's ability to modify chromatin structure and access new regions allows it to spread across the X-chromosome. The study also demonstrates that Xist's localization is influenced by the 3D conformation of the X-chromosome, with early localization sites determined by spatial proximity to the Xist transcription locus. The results suggest a model where Xist searches in three dimensions, modifies chromosome structure, and spreads to newly accessible locations. This process enables Xist to silence the entire X-chromosome reproducibly, despite variations in chromosome conformation between individual cells. The findings highlight the importance of 3D genome architecture in the function of lncRNAs and suggest that other lncRNAs may similarly use chromosome conformation to identify target sites.Xist is a long non-coding RNA (lncRNA) that plays a critical role in X-chromosome inactivation (XCI), a process that silences one of the two X chromosomes in female mammals. This study reveals that Xist spreads across the X-chromosome by exploiting three-dimensional (3D) genome architecture. During XCI initiation, Xist initially localizes to distal regions of the X-chromosome that are not defined by specific sequences but by their spatial proximity to the Xist transcription locus. Xist then spreads across the chromosome by modifying chromatin structure and accessing newly accessible regions. The silencing domain of Xist is essential for spreading across actively transcribed regions and accessing the entire chromosome. The study also shows that Xist localizes to the periphery of actively transcribed regions and gradually spreads into them through the A-repeat domain. Xist's ability to modify chromatin structure and access new regions allows it to spread across the X-chromosome. The study also demonstrates that Xist's localization is influenced by the 3D conformation of the X-chromosome, with early localization sites determined by spatial proximity to the Xist transcription locus. The results suggest a model where Xist searches in three dimensions, modifies chromosome structure, and spreads to newly accessible locations. This process enables Xist to silence the entire X-chromosome reproducibly, despite variations in chromosome conformation between individual cells. The findings highlight the importance of 3D genome architecture in the function of lncRNAs and suggest that other lncRNAs may similarly use chromosome conformation to identify target sites.