Synovial sarcoma is a unique tumor with substantial promise for biologically targeted therapy. Although it demonstrates moderate chemosensitivity, with approximately 50% response rates to ifosfamide- and doxorubicin-containing regimens, it has a diagnostic translocation and a potentially informative chimeric protein product. Although surgical management remains the cornerstone to effect local control, therapeutic advancements are unlikely to occur by continuing to include advanced cases of synovial sarcomas in trials with other soft tissue sarcomas. Rather, attention should be turned toward prospective molecular targets and development of novel agents to exploit them. Research should be directed at understanding the fusion protein of the X,18 translocation and further validating the role of overexpressed proteins in synovial sarcoma. Meanwhile, carefully designed clinical trials of these agents, with translational correlates, will provide in vivo data to complement the preclinical experience.