Multiple lines of evidence have suggested that the SS18/SSX fusion is an oncogene and the central genetic “driver” in SS; (i) its presence as a sole cytogenetic anomaly in up to one-third of cases [9, 10], (ii) the low frequency of additional mutations [9, 11], (iii) its preservation in metastatic and advanced lesions [9, 10], (iv) the death of synovial sarcoma cells upon SS18/SSX knockdown [9, 12], and (v) its ability to induce tumors in conditional mouse models with appropriate histology, gene expression, and immunophenotype with 100% penetrance [9, 13]. This evidence concerns the gene SS18 and synovial sarcoma.