A genome-scale pan-cancer screening approach using CasRx was developed to investigate long noncoding RNA (lncRNA) dependencies. The study overcomes limitations of existing methods by targeting RNA directly, enabling efficient and specific lncRNA interrogation. A size-reduced multiplexed gRNA library, Albarossa, targeting 24,171 lncRNA genes, was designed with prioritization based on expression, evolutionary conservation, and tissue specificity. This library allows for high-throughput screening across multiple cancer types, identifying both context-specific and common essential lncRNAs. The CasRx system, which targets RNA without causing off-target DNA cleavage, was optimized for genome-wide screening, demonstrating high specificity and efficiency. The study shows that CasRx-based screening outperforms other methods, such as CRISPRi, in terms of off-target effects and scalability. The Albarossa library was validated across multiple cancer cell lines, revealing lncRNA dependencies with high accuracy and specificity. The results highlight the importance of lncRNA in cancer biology and provide a framework for systematic exploration of lncRNA function in health and disease. The study also addresses challenges in lncRNA annotation and tissue-specific expression, offering a robust platform for pan-cancer lncRNA research. The findings contribute to the understanding of lncRNA vulnerabilities and their potential as therapeutic targets.A genome-scale pan-cancer screening approach using CasRx was developed to investigate long noncoding RNA (lncRNA) dependencies. The study overcomes limitations of existing methods by targeting RNA directly, enabling efficient and specific lncRNA interrogation. A size-reduced multiplexed gRNA library, Albarossa, targeting 24,171 lncRNA genes, was designed with prioritization based on expression, evolutionary conservation, and tissue specificity. This library allows for high-throughput screening across multiple cancer types, identifying both context-specific and common essential lncRNAs. The CasRx system, which targets RNA without causing off-target DNA cleavage, was optimized for genome-wide screening, demonstrating high specificity and efficiency. The study shows that CasRx-based screening outperforms other methods, such as CRISPRi, in terms of off-target effects and scalability. The Albarossa library was validated across multiple cancer cell lines, revealing lncRNA dependencies with high accuracy and specificity. The results highlight the importance of lncRNA in cancer biology and provide a framework for systematic exploration of lncRNA function in health and disease. The study also addresses challenges in lncRNA annotation and tissue-specific expression, offering a robust platform for pan-cancer lncRNA research. The findings contribute to the understanding of lncRNA vulnerabilities and their potential as therapeutic targets.