Recent advance in autoimmunity research reveals that the innate immune system is able to recognize self-targets and initiate inflammatory response in a similar way as with pathogens. This review describes one novel example of this innate autoimmunity, ischemia-reperfusion (I/R) injury. Studies of intestinal, skeletal muscle, and heart I/R models showed that reperfusion of ischemic tissues elicits an acute inflammatory response involving serum complement system which is activated by natural IgM. The recent identification of a monoclonal natural IgM that initiates I/R led to the identification of non-muscle myosin heavy chain type II A and C as the self-targets in two different tissues. New evidence further suggests that IgM binds initially to ischemic antigen providing a binding site for mannan binding lectin (MBL) which subsequently leads to activation of complement and results in tissue injury. Therefore, natural IgM mediated innate autoimmunity is likely responsible for the detrimental consequences in ischemic diseases.