This study presents a comprehensive analysis of the mutational landscape of metastatic cancer through a large-scale, prospective clinical sequencing initiative. The MSK-IMPACT assay, a hybridization capture-based next-generation sequencing (NGS) panel, was used to sequence tumor and normal DNA from over 10,000 patients with advanced cancer. The dataset includes matched tumor and normal sequence data, enabling the identification of clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures. Key findings include: 1. **Genomic Profiling Feasibility**: The study demonstrates the feasibility and utility of large-scale prospective clinical sequencing, achieving an average throughput of 563 cases per month with a median turnaround time of <21 days. 2. **Diverse Tumor Types**: The cohort encompasses 62 principal tumor types and over 300 detailed tumor types, providing a rich dataset for understanding the prevalence of driver alterations across all cancers. 3. **Clinical Utility**: 36.7% of patients harbored at least one actionable alteration, and 11% of the first 5,009 patients tested were enrolled on genomically matched clinical trials. This highlights the potential for broad molecular profiling to guide treatment decisions. 4. **Novel Mutations and Fusions**: The study identified novel mutations and fusions, including a novel recurrent *BRAF* fusion, which may have therapeutic implications. 5. **Mutation Signatures and Somatic Hypermutation**: The presence of mutation signatures, such as those associated with DNA repair defects and exposure to exogenous mutagens, was identified, providing insights into disease etiology and response to therapies. 6. **Clinical Impact**: The study emphasizes the importance of broad molecular profiling to identify novel biomarkers and develop more effective treatment options, particularly for patients with advanced and heavily treated cancers. The full dataset is publicly available through the cBioPortal for Cancer Genomics, facilitating further research and clinical applications.This study presents a comprehensive analysis of the mutational landscape of metastatic cancer through a large-scale, prospective clinical sequencing initiative. The MSK-IMPACT assay, a hybridization capture-based next-generation sequencing (NGS) panel, was used to sequence tumor and normal DNA from over 10,000 patients with advanced cancer. The dataset includes matched tumor and normal sequence data, enabling the identification of clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures. Key findings include: 1. **Genomic Profiling Feasibility**: The study demonstrates the feasibility and utility of large-scale prospective clinical sequencing, achieving an average throughput of 563 cases per month with a median turnaround time of <21 days. 2. **Diverse Tumor Types**: The cohort encompasses 62 principal tumor types and over 300 detailed tumor types, providing a rich dataset for understanding the prevalence of driver alterations across all cancers. 3. **Clinical Utility**: 36.7% of patients harbored at least one actionable alteration, and 11% of the first 5,009 patients tested were enrolled on genomically matched clinical trials. This highlights the potential for broad molecular profiling to guide treatment decisions. 4. **Novel Mutations and Fusions**: The study identified novel mutations and fusions, including a novel recurrent *BRAF* fusion, which may have therapeutic implications. 5. **Mutation Signatures and Somatic Hypermutation**: The presence of mutation signatures, such as those associated with DNA repair defects and exposure to exogenous mutagens, was identified, providing insights into disease etiology and response to therapies. 6. **Clinical Impact**: The study emphasizes the importance of broad molecular profiling to identify novel biomarkers and develop more effective treatment options, particularly for patients with advanced and heavily treated cancers. The full dataset is publicly available through the cBioPortal for Cancer Genomics, facilitating further research and clinical applications.