Synovial sarcoma is a high-grade soft tissue malignancy characterized by a unique fusion gene known as SS18-SSX. The SS18-SSX fusion protein acts as an oncogenic driver of synovial sarcoma, and it has thus been commonly accepted that disruption of SS18-SSX function represents a therapeutic means of treating synovial sarcoma, but emerging evidence suggests that upon depletion of SS18-SSX, an anti-apoptotic signal surprisingly arises to protect synovial sarcoma cell survival. In this article, we discuss the controversial roles of SS18-SSX’s transcriptional activity in synovial sarcoma biology and outline a synergistic strategy for overcoming the resistance of synovial sarcoma cells to SS18-SSX targeted therapeutics.