Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is a neoplasm that typically occurs in the first and second decades of life but may present from infancy to late middle age. ES/PNET generally arises in bone or soft tissue, and examples have been described at most sites. The pathologic nature is defined by a combination of histology, immunohistochemistry, ultrastructure, and molecular genetic abnormalities. The lesions variously termed Ewing's sarcoma, (peripheral) primitive neuroectodermal tumor, peripheral neuroepithelioma, peripheral neuroblastoma, and Askin tumor have been characterized in the past as distinct entities. However, currently all are considered to be members of a common tumor family, the ES/PNET group, which share a limited set of genetic abnormalities defined by fusions of the EWS gene on chromosome 22 with a member of the ets family of transcription factors, most commonly the FLI1 gene on chromosome 11. Neural differentiation is often expressed by ES/PNET, representing the PNET end of the morphologic spectrum. This feature has been linked with clinical outcome, but differences in behavior on the basis of histology are largely overshadowed by clinical prognostic factors: older age, larger size, central site, and presence of metastases all correlate much more powerfully with poor outcome than any single pathologic feature. Recently, specific differences in chromosomal breakpoint fusion type have been closely related to clinical outcome, and this relationship holds great promise for prognostication in the future.