Important and meaningful advances have been made in mesenchymal tumor cytogenetics during the last two decades. A number of bone and soft tissue tumors have been shown to have recurrent, if not specific, chromosomal changes, particularly translocations. These changes not only serve as aids in the diagnosis and classification of bone and soft tissue tumors, especially in the differential diagnosis of those of confusing nature, but have also guided molecular studies in establishing the underlying genes involved. To date, a number of tumor-specific gene fusions have been identified and many have been shown to encode aberrant transcription factors. These key biological events in bone and soft tissue tumors are crucial not only to our understanding of the sarcomagenetic processes leading to the various tumors, but also ultimately in the design of specific therapies tailored to the genetic events in mesenchymal neoplasms.