Background: Sarcomas consist of a broad family of mesenchymal malignancies with remarkable diversity. Currently, there are no targeted drugs approved for sarcomas except for pazopanib and imatinib. In this study, comprehensive genomic profiling of 221 sarcomas by targeted next generation sequencing (NGS) was performed, the clinical relevant genomic alterations (CRGAs) and potential therapeutic targets were explored. Methods: 211 sarcomas, including 30 leiomyosarcoma (LMS), 13 osteosarcoma (OS), 13 rhabdomyosarcoma (RMS), 9 synovial sarcoma (SS), 22 liposarcoma (LPS), and 124 other subtypes were sequenced by cancer gene panel (CGP) with all coding exons and splicing sites of 365 cancer-related genes plus selected introns from 25 frequently rearranged genes. Genomic alterations (GAs) including point mutations, short insertions and deletions, copy number variations, and rearrangements were called, and further confirmed manually using IGV. These CRGAs were annotated based on literature review and some of them are actionable. Results: There are 1215 GAs for all 211 sarcomas and average 5.5 mutations per sample. Among these subtypes, LPS has the highest number of mutations per sample (average 7.5), SS has the lowest number of mutations per sample (average 2.7). Interestingly, 49% GAs are structure variations (SVs). In addition, the top ranked altered genes were TP53 (36%), RB1 (13%), MDM2 (12%) and CDK4 (11%) in all sarcomas. The genomic alterations across all subtypes of sarcomas are enriched in cell cycle pathway. Furthermore, 88% of patients have at least one CRGA, 10 patients with CRGAs in FGFR1/2/3, VEGFA, KIT, FLT4 or KDR could benefit from pazopanib. 57 patients have at least one actionable mutation. Among them, 24 patients with CRGAs in CDK4, CDKN2A/B could benefit from palbociclib, 22 patients with CRGAs in MTOR, PIK3CA, NF1/2, PTEN, TSC1 or STK11 could benefit from everolimus, and 6 patients with CRGAs in BRCA2, ARD1A or ATM could benefit from olaparib. Conclusions: This study demonstrated that sarcomas are characterized predominantly by structure variations, most of sarcomas have at least one actionable mutation. In conclusion, comprehensive genomic profiling in a large cohort highlights the promise of targeted therapies.