Soft tissue sarcoma (STS), although heterogeneous in histopathology presentation, has mostly been treated with chemotherapy agents as one entity. Our understanding of crucial genomic alterations in different STS histologies and the advent of molecular-targeted agents have reshaped the treatment paradigm for advanced STS. Small-molecule inhibitors of c-KIT, plate-derived growth factor receptor alpha, c-MET, BRAF, anaplastic lymphoma kinase, ROS1 and colony-stimulating factor-1 receptor have been successfully validated in clinical studies to yield practice-changing results. Inhibitors of other novel genomic targets including mouse double minute 2 homolog, cyclin-dependent kinase 4/6, mitogen-activated protein kinase and epigenetic regulators are expected to be developed in the near future. Furthermore, with the advancement and accessibility of molecular diagnosis and next-generation sequencing, a genomic-based therapeutic approach should be widely applicable to advanced STS patients. This review will focus on the progress of genomic-guided therapy tailored to each molecular alteration of different STS histologies.

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