Somatic mutations, often translocations or single nucleotide variations, are pathognomonic for certain types of cancers and are increasingly of clinical importance for diagnosis and prediction of response to therapy. Conventional clinical assays only evaluate 1 mutation at a time, and targeted tests are often constrained to identify only the most common mutations. Genome-wide or transcriptome-wide high-throughput sequencing (HTS) of clinical samples offers an opportunity to evaluate for all clinically significant mutations with a single test. Recently a "desktop version" of HTS has become available, but most of the experience to date is based on data obtained from high-quality DNA from frozen specimens. In this study, we demonstrate, as a proof of principle, that translocations in sarcomas can be diagnosed from formalin-fixed paraffin-embedded (FFPE) tissue with desktop HTS. Using the first generation MiSeq platform, full transcriptome sequencing was performed on FFPE material from archival blocks of 3 synovial sarcomas, 3 myxoid liposarcomas, 2 Ewing sarcomas, and 1 clear cell sarcoma. Mapping the reads to the "sarcomatome" (all known 83 genes involved in translocations and mutations in sarcoma) and using a novel algorithm for ranking fusion candidates, the pathognomonic fusions and the exact breakpoints were identified in all cases of synovial sarcoma, myxoid liposarcoma, and clear cell sarcoma. The Ewing sarcoma fusion gene was detectable in FFPE material only with a sequencing platform that generates greater sequencing depth. The results show that a single transcriptome HTS assay, from FFPE, has the potential to replace conventional molecular diagnostic techniques for the evaluation of clinically relevant mutations in cancer.