Hematopathology is the backbone of diagnosis of all hematologic and bone marrow diseases and as such is crucial for categorizing disease, designing treatment, following results, and comparing regimens. Precise hematopathology diagnosis is central to understanding the underlying molecular pathophysiology of disease and thereby in revealing potential new targets for experimental therapy. The issues in hematopathologic diagnosis are much more intricate in children compared with adults because pathology changes with physiology—thus, as the child develops, the types of hematopoietic disease vary not just by age and developmental stage of the child but also by age and stage of the affected organ. Additionally, some congenital syndromes diagnosed in childhood are associated with hematopoietic conditions that may appear malignant to the untrained observer but actually may be benign and even transient, as occurs in patients with Down syndrome. Also, a number of “small round blue cell tumors,” eg, neuroblastoma, Ewing sarcoma, or rhabdomyosarcoma, may masquerade as leukemia and require expert analysis for correct identification. These and other quandaries are unique to pediatrics and pivotal to proper diagnosis and treatment.