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Antibodies capable to recognize antigen expressed on cancer cells represents the ideal approach for targeted anti neoplastic therapies. The CD33 antigen is present on 90% of acute myeloid leukemia blasts and is shared on normal hemopoietic cells only on the non stem dillerentiating fraction. Gemtuzumab Ozogamicin (GO) is an engineered humanized antibody anti-CD33 conjugated with a potent intercalating agent, named calicheamicin, which is release only at intracellular level (lower pH), following a selective binding to CD33-positive cells, thus representing a promising approach for target anti-leukemia therapy. GO was approved conditionally by the Federal Drug Administration in May 2000 as a single therapy for first recurrence of Acute Myeloid Leukemia (AML) in a subset of older patients. Since 2000, treatment trials and pilot studies have revealed potential expanded applications along with potential limitations. Phase II trials have confirmed the activity and the efficacy of GO as single agent in the treatment of relapsed AML. More recently, clinical trials on induction and post-remission treatment of adult AML have shown efficacy of GO in combination chemotherapy. The strong and homogeneous CD33 expression in Acute Promyelocytic Leukemia (APL), have resulted in an effective treatment of this disease with GO used as salvage treatment, as well as innovative approach for molecular relapsed patients. However, the incidence of veno-occlusive disease, better defined as sinusoidal occlusive syndrome (SOS), must be taken into account as potential complication associated with the GO administration, especially in patients treated with ablative regimens. In conclusion, the extension of the approval in Italy to AML CD33+ in relapsed, regardless age limitation, along with the ongoing evaluation by the European EMEA, represent the basis for a large clinical application of GO in myeloid malignancies potentially extended to paediatric patients with AML and to ALL CD33+.