Acute promyelocytic leukemia (APL) is, at present, the first and only example of leukemia which can be induced into remission with a single cyto-differentiating agent. This is due to the fact that APL is exquisitely sensitive to the differentiating action of all-trans retinoic acid (ATRA). Thus, the APL model offers a unique opportunity to study the cyto-differentiating action of ATRA and synthetic retinoids in a clinically relevant setting. This review article summarizes the work relating to the molecular mechanisms underlying the action of retinoic acid and retinoids in APL cells, and focuses on: a) genes which are expressed and regulated by ATRA; b) synthetic retinoids as cyto-differentiating agents; c) rational combinations between retinoids and cytokines or other cyto-differentiating agents; d) cellular paradigms of retinoic acid resistance. It is our aim to give an updated, about nonexhaustive, account of some of the most recent development regarding the pharmacological action of retinoic acid and its derivatives in APL cells.