The differential diagnosis of small round cell tumors includes not only the small round cell tumors of infancy and childhood, but a variety of mesenchymal, cutaneous, and lymphoreticular neoplasms that may occur in adults as well as children. Moreover, lesions considered to be the classical small round cell tumors of childhood may occasionally occur in adults, and lesions characteristically seen in adults may at times occur in children. An awareness of the diverse lesions that may present as small round cell tumors is critical to arrive at the correct diagnosis. Immunohistochemical techniques and ultrastructural studies have now become indispensable in the diagnosis of small round cell tumors. With recent developments in cytogenetic and molecular genetic techniques, the pathologist has acquired an even more powerful and precise armamentarium of diagnostic tools. Judicious use of these methods, with knowledge of their significance and limitations, is the responsibility of the pathologist and laboratory coworkers who play a pivotal role in patient care and treatment. The differential diagnosis of small round cell tumors, including adult-type sarcomas, lymphoreticular malignancies, and neuroectodermal tumors of skin and viscera that simulate classical small round cell tumors, is briefly reviewed with this perspective. Specific cytogenetic and molecular markers are covered in addition to the typical immunohistochemical and ultrastructural features of several diverse lesions.