Soft tissue sarcomas represent a heterogeneous group of malignancies with over 100 distinct subtypes. Next-generation sequencing has transformed sarcoma diagnostics by helping to identify pathognomonic molecular alterations that define specific entities and guide therapeutic decisions. Molecular characterization is now an integral part of WHO classification, establishing definitive criteria for several entities that cannot be reliably distinguished by morphology or immunohistochemistry alone. This chapter provides a comprehensive molecular classification framework organizing sarcomas according to their primary genetic mechanisms: fusion-driven tumors with chimeric transcription factors or receptor tyrosine kinases, non-fusion kinase-activated sarcomas, tumors with complex genomic profiles, and epigenetically deregulated entities. The therapeutic implications extend beyond diagnostic precision, with targeted therapies for ALK, NTRK, and other kinase-driven sarcomas. Challenges remain including intratumoral heterogeneity, limited access to molecular testing, and the rarity of individual subtypes. Integration of NGS with emerging technologies promises to further improve diagnosis, prognostication, and personalized treatment selection for these complex malignancies.