Acute pancreatitis (AP) is a common emergency condition. In the majority of cases, it presents in a mild and self-limited form. However, about 20% of patients develop severe disease with local pancreatic complications (including necrosis, abscess, or pseudocysts), systemic organ dysfunction, or both. A modern classification of AP severity has recently been proposed based on the factors that are causally associated with severity of AP. These factors are both local (peripancreatic necrosis) and systemic (organ failure). In AP, inflammation is initiated by intracellular activation of pancreatic proenzymes and/or nuclear factor-κB. Activated leukocytes infiltrate into and around the pancreas and play a central role in determining AP severity. Inflammatory reaction is first local, but may amplify leading to systemic overwhelming production of inflammatory mediators and early organ failure. Concomitantly, anti-inflammatory cytokines and specific cytokine inhibitors are produced. This anti-inflammatory reaction may overcompensate and inhibit the immune response, rendering the host at risk for systemic infection. Currently, there is no specific treatment for AP. However, there are several early supportive treatments and interventions which are beneficial. Also, increasing the understanding of the pathogenesis of systemic inflammation and the development of organ dysfunction may provide us with future treatment modalities.