It has been shown in vitro that retinoids and especially all-trans retinoic acid (ATRA) were able to induce maturation of malignant cells from patients with acute promyelocytic leukemia (APL). Clinical studies have confirmed in vitro observations. Oral administration of ATRA is able to induce complete remissions in the majority of APL patients, either treated de novo or after failure of conventional chemotherapy. Complete remission are observed by a differentiation process and ATRA therapy in APL represents the first model of differentiation therapy. The major adverse effect of ATRA treatment is the occurrence in some cases of a "retinoic acid syndrome" associated with rapidly, progressive rise of leukocytes. This syndrome is corrected by the addition of chemotherapy. A progressive acquired resistance appears during ATRA treatment and for this reason post remission chemotherapy is indispensable. The superiority of the combination of ATRA+chemotherapy over chemotherapy alone for the incidence of relapse and for survival duration has been established in a randomized European trail (APL 91).