Since the introduction of all-trans retinoic acid, the use of this molecularly targeted treatment in combination with anthracycline-based chemotherapy has completely changed the prognosis of acute promyelocytic leukemia, turning it into the most curable myeloid leukemia. Also, the use of risk-adapted protocols has contributed to optimizing the drug combination and the most appropriate dose intensity for each subset of patients classified according to both the risk of relapse and vulnerability to drug toxicity. Recent developments have included the investigation of the role of arsenic trioxide as front-line treatment after its success in treating relapsed APL, both to minimize or even omit the use of cytotoxic agents and to improve the outcome of the conventional chemotherapy-based approach. In this review, we discuss the current treatment approach for acute promyelocytic leukemia in newly diagnosed patients, particularly taking into account the latest developments with the use of the arsenic trioxide based regimen as targeted first-line treatment without chemotherapy.