PURPOSE: To discuss the predisposing risk factor for all forms of extramedullary leukemia (EML) and to review the clinical features, prognostic significance, and treatment strategies for primary EML and leukemia cutis (LC)/granulocytic sarcomas (GS) in the setting of acute nonlymphocytic leukemia (ANLL). METHODS: A review of all reports published since 1965 related to all forms of extramedullary leukemia (LC, GS, gingival hypertrophy, and meningeal leukemia [ML]). RESULTS: Several factors, including chromosomal abnormalities [t(8;21), inv(16)], cell-surface markers (CD56, CD2, CD4, CD7), French-American-British (FAB) subtype (M2, M4, M5), blast differentiation and maturation, patient nutritional status, age, cellular immune dysfunction, high presenting leukocyte count, and decreased blast Auer rods, have been associated with a higher incidence of EML. Of 154 published cases of primary EML identified, 71 (46%) were initially misdiagnosed. The addition of immunohistochemical stains can assist in preventing such misdiagnoses and should be included in all atypical lymphoma/carcinoma cases. Only one of the patients (3%) with primary EML did not progress to ANLL in the absence of chemotherapy. In contrast, 66% of patients who received chemotherapy for the primary EML never developed ANLL. The prognostic significance of EML at presentation and medullary relapse of ANLL is uncertain. Isolated extramedullary recurrence of ANLL always heralds bone marrow relapse and should be treated with reinduction chemotherapy. Close clinical follow-up observation is necessary to insure resolution of EML. Radiation therapy is an effective local treatment for resistant or symptomatic EML. CONCLUSION: Many advances in diagnoses and treatment of EML have been made. Future investigations are needed to define the clinical significance of EML in patients with ANLL treated with modern chemotherapy or bone marrow transplantation.