Soft-tissue sarcomas are tumors of mesenchymal origin that often constitute a diagnostic and therapeutic dilemma. Some soft-tissue sarcomas are characterized by specific chromosomal translocations. The resulting fusion transcripts typically encode aberrant transcription factors, and their pathogenic effects are likely to be mediated through their actions on gene expression. Based on this hypothesis we are investigating gene expression patterns in synovial sarcoma using complementary DNA microarrays containing 6,500 sequence-verified human cDNAs. The t(X; 18)(p11.2; q11.2) translocation is characteristic of synovial sarcomas and fuses the SYT gene to either SSX1 or SSX2. Expression analyses were performed on 16 synovial sarcomas confirmed to have either the SYT–SSX1 or SYT–SSX2 fusion transcript. Five other sarcoma samples, mostly malignant fibrous histiocytomas, were included as a comparison group. Hierarchical clustering analysis shows that these two tumor groups clearly separate with distinct expression patterns. One of the tumors, previously diagnosed as a synovial sarcoma, was closer to the malignant fibrous histiocytoma cluster. Analysis by means of the polymerase chain reaction with reverse transcription showed that this tumor was lacking the SYT–SSX fusion transcript, and the histological review reclassified it as a fibrosarcoma. This indicates that SYT–SSX-verified synovial sarcomas indeed have a specific expression profile. We are now attempting to determine the genes best able to define the synovial sarcoma cluster. Synovial sarcomas have two major histological subtypes, biphasic and monophasic, defined by the presence or absence of glandular epithelial differentiation in a background of spindle cells. Analyses of the genes discriminating monophasic from biphasic synovial sarcomas may also provide clues to the pathways regulating epithelial differentiation.