Described herein is the evolution in the diagnosis and classification of tumors that are variously known as blastic or blastoid natural killer cell lymphoma, CD4+/CD56+ hematodermic neoplasm, or tumors of plasmacytoid dendritic cell lineage. As illustrated by cases submitted to the 2005 Society for Hematopathology/European Association for Haematopathology Workshop, these tumors display a range of clinical manifestations and various morphologic and immunophenotypic features. Recent evidence suggests a close histogenetic relationship for most cases to plasmacytoid dendritic cells. We outline the typical presenting features and the clinical course of CD4+/CD56+ hematodermic tumors, including leukemic relapses with shifts to myelomonocytic differentiation. The currently unresolved issues are largely related to the limits of this entity, particularly the relationship to myeloid leukemia and undifferentiated blastic neoplasms, with which there is diagnostic overlap. Although questions remain, delineation of the CD4+/CD56+ hematodermic tumor and its improved recognition has already served as a catalyst toward better understanding of the multilineage potential of hematopoietic malignancies.