Much controversy surrounds the pathogenesis of acetaminophen-induced inflammation. Acetaminophen (APAP) is a well-studied xenobiotic that in high doses results in a deadly, yet preventable, form of liver failure. Although its effects are sudden and often irreversible, its mechanism is far from simple. In fact, at first glance, recent studies seem to refute each other. The field has been grappling with seemingly contradictory results driven mainly by often-generalized assumptions and different experimental systems. As always, the devil—or in this case, liver failure—is in the details. In this paper, Tang and colleagues identified macrophage-derived interleukin (IL)-1α as a mediator of sterile inflammation in a mouse model of APAP hepatotoxicity. IL-1α is an alarmin that unlike IL-1β, is constitutively expressed in many cells as a precursor. IL-1α precursor (pre-IL-1α) is active as a damage-associated molecular pattern (DAMP). After enzymatic cleavage, mature IL-1α can signal a more potent pro-inflammatory message.