Diagnostic classification of poorly differentiated, round cell, primitive neuroectodermal neoplasms, including Ewing's sarcoma, peripheral neuroepithelioma, Askin's tumor, and esthesioneuroblastoma, is challenging to the surgical pathologist using conventional histopathologic approaches because of very similar and overlapping morphologic and cytologic features. Furthermore, distinguishing these neoplasms from neuroblastoma, embryonal rhabdomyosarcoma, small cell osteogenic sarcoma, and non-Hodgkin's lymphoma can be difficult. This paper describes and reviews the cytogenetic and molecular genetic changes in these tumors and demonstrates how the ability to detect these changes has enabled a greater understanding of the histogenesis, classification, diagnosis, and prognosis of these neoplasms.