The Cancer Cell Line Encyclopedia (CCLE) has expanded its characterization to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression, and reverse-phase protein array data for 1,072 cell lines from various lineages and ethnicities. This comprehensive dataset integrates functional characterizations such as drug sensitivity, short hairpin RNA knockdown, and CRISPR-Cas9 knockout data to identify potential targets for cancer drugs and associated biomarkers. The CCLE portal and accompanying public data portal provide a resource to accelerate cancer research using model cancer cell lines. The study also includes detailed methods for various analyses, such as variant calling, structural variant analysis, fusion detection, mutational signature analysis, and MSI annotations. These advancements enhance the understanding of molecular dysregulations in cancer and their implications for therapeutic intervention.The Cancer Cell Line Encyclopedia (CCLE) has expanded its characterization to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression, and reverse-phase protein array data for 1,072 cell lines from various lineages and ethnicities. This comprehensive dataset integrates functional characterizations such as drug sensitivity, short hairpin RNA knockdown, and CRISPR-Cas9 knockout data to identify potential targets for cancer drugs and associated biomarkers. The CCLE portal and accompanying public data portal provide a resource to accelerate cancer research using model cancer cell lines. The study also includes detailed methods for various analyses, such as variant calling, structural variant analysis, fusion detection, mutational signature analysis, and MSI annotations. These advancements enhance the understanding of molecular dysregulations in cancer and their implications for therapeutic intervention.