Extracorporeal membrane oxygenation (ECMO) results in widespread activation of the innate immune system in response to blood contact with the nonendothelialized surface. This reaction is similar to the systemic inflammatory response syndrome (SIRS) and can result in widespread inflammation and tissue damage and may affect the function and longevity of the circuit. The pathophysiology of the inflammatory and coagulative processes involving the complex interplay of the contact system and complement and leukocyte activation are reviewed here. An understanding of these events allows for a tailored approach to current and future treatment modalities, including circuit modifications, novel pharmaceuticals, and blood purification devices.