The Annonaceous acetogenins (ACG) are a large group of natural products isolated from a few number of generus of the Annonaceae family (Annona, Asimina, Goniothalamus, Rollinia, Xylopia, Uvaria and more recently from Polyalthia, Porcelia and Disepalum). Since uvaricin was isolated from Uvaria acuminata roots in 1982, more that 300 acetogenins have been described. These compounds are powerful cytotoxics, with potential applications as insecticides, antiparasitics, acaricides, fungicides, and as a highly interesting new generation of antitumour drugs. Great effort has been made from several directions to elucidate the mode of action of the Annonaceous acetogenins. Herein we review the most recent work made in this field from an enzymatic point of view.