This study presents a comprehensive approach to prioritize oncology therapeutic targets using CRISPR-Cas9 screens in 204 human cancer cell lines from 12 cancer types. The authors developed a data-driven framework that integrates gene cell fitness effects, genomic biomarkers, and target tractability to systematically identify new oncology targets. They identified 497 unique priority targets, including 83 pan-cancer and 470 cancer-type-specific targets. The framework also assessed the tractability of these targets for drug development, categorizing them into three groups based on their potential for pharmaceutical intervention. Notably, the *WRN* gene, encoding Werner syndrome RecQ-like helicase, was identified as a promising target in cancers with microsatellite instability (MSI-H). The study provides a rich resource for future research and drug development, aiming to improve the success rates and effectiveness of oncology therapies.This study presents a comprehensive approach to prioritize oncology therapeutic targets using CRISPR-Cas9 screens in 204 human cancer cell lines from 12 cancer types. The authors developed a data-driven framework that integrates gene cell fitness effects, genomic biomarkers, and target tractability to systematically identify new oncology targets. They identified 497 unique priority targets, including 83 pan-cancer and 470 cancer-type-specific targets. The framework also assessed the tractability of these targets for drug development, categorizing them into three groups based on their potential for pharmaceutical intervention. Notably, the *WRN* gene, encoding Werner syndrome RecQ-like helicase, was identified as a promising target in cancers with microsatellite instability (MSI-H). The study provides a rich resource for future research and drug development, aiming to improve the success rates and effectiveness of oncology therapies.