With the availability of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML), has gained a new and exemplary importance. So far, therapeutic strategies in oncology have been directed against the increased proliferative activity of the neoplastic cell clone. Treatment of APL with ATRA is a good example for successful ‘tumor differentiating therapy’. Under the influence of ATRA, immature leukemic cells differentiate into more mature leukemic cells which lack mitotic activities. Due to the physiological death of these maturing leukocytes, indirect reduction of tumor cell burden is achieved, and the majority of APL patients enter complete remission. It is of particular interest that bone marrow aplasia which is the main side effect of conventional chemotherapy can be avoided. Nevertheless, treatment of APL with ATRA is not devoid of clinical problems. Treatment with ATRA leads to a ‘washout’ of maturing promyelocytic blast cells which may cause hyperleukocytosis. Particularly during the early phases of treatment, this may contribute to the occurrence of severe thromboembolic events. Thus, the clinical picture of APL may change from hemorrhagic complications to leukostasis and thromboembolism. Evaluation of risk factors for the development of hyperleukocytosis is of critical importance for the patient. In order to avoid life-threatening complications, an effective prophylaxis of thromboembolism and in some cases additional chemotherapy may be necessary.