A key issue in studying mammalian DNA base excision repair is how its component proteins respond to a plethora of cell-signaling mediators invoked by DNA damage and stress-inducing agents such as reactive oxygen species, and how the actions of individual BER proteins are attributed to cell survival or apoptotic/necrotic death. This article reviews the past and recent progress on posttranslational modification (PTM) of mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1).