The acute inflammatory response is composed of an elaborate cascade of both proinflammatory and anti-inflammatory mediators. The balance between these mediators often determines the outcome after injury. In clinical scenarios, such as trauma or sepsis, there is often unregulated production of proinflammatory mediators that can cause multiple organ failure. Further understanding of the endogenous mechanisms that control the inflammatory response is needed to facilitate development of therapeutic options. In this review, we discuss the current knowledge of the mechanisms leading to development of acute inflammatory injury as well as the factors that regulate this response.