The precise etiology for most sarcomas remains unknown. External radiation therapy is an established risk factor. Other risk factors include occupational exposures to certain chemicals, lymphedema, and hereditary conditions such as neurofibromatosis and Li-Fraumeni syndrome. Many sarcomas are associated with specific somatic genetic alterations. For example, some specific subtypes are associated with gene translocations causing aberrant fusion proteins including Ewing sarcoma (EWS-FLI-1), synovial sarcoma (SSX-SYT), alveolar rhabdomyosarcoma (PAX3-FHKR), and myxoid liposarcomas (TLS-CHOP). These singular molecular alterations imply that some sarcomas are cytogenetically simple and may be more appropriate substrates for therapy targeted to a single molecular pathway.