During last decades acute promyelocytic leukemia, once considered the deadly disease, has evolved to the most treatable of all subtypes of acute myeloid leukemias. The intense clinical and basic research has led to a rational approach to treatment in which the use of the differentiating agent all-trans-retinoic acid has proven to be effective first-line therapy. Arsenic trioxide, used for relapsed disease, further improved the survival rate of patients. The classical model presented the therapeutic success as a result of over-coming of the differentiation block characteristic of neoplastic cells. However, the resent in vivo and ex vivo studies, seem to show that the induction of differentiation process is not required to cure acute promyelocytic leukemia. Rather than inducing differentiation, targeting clonogenic leukemia initiating cells or destroying PML-RARa fusion protein may represent a more effective therapeutic goal in this type of leukemia.