Synovial sarcoma is a distinct tumor with unique promise for targeted therapy. It has a diagnostic translocation and a potentially informative fusion protein. It has moderate chemosensitivity, with about 50% response rates to regimens containing ifosfamide and doxorubicin. Therapeutic advances are unlikely to occur by continuing to lump synovial sarcomas in trials with other soft tissue sarcomas and adjusting traditional agents; rather, attention should be turned toward prospective molecular targets and investigation or development of novel agents to exploit them. The SYT-SSX fusion protein that results from the X,18 translocation is an appealing target, as are the proteins overexpressed in synovial sarcoma: bcl-2, EGFR, and HER-2/neu.