Recent studies showed that innate autoimmunity is an early mechanism for ischemia-reperfusion (I/R) injury. Results from different animal models showed that reperfusion of ischemic tissues elicits an acute inflammatory response involving a complement system, which is activated by autoreactive natural IgM. Moreover, ischemia-specific self-targets were identified. In contrast to the unsuccessful attempts in the past to treat I/R injury, targeting natural IgM-mediated innate autoimmunity may open a new avenue for early intervention.