A large body of clinical and experimental evidence suggests that cytokines play a key role in the pathogenesis of local and systemic complications of acute pancreatitis. IL-18 is a pro-inflammatory cytokine that plays a key role in many human diseases, including acute pancreatitis. This review focuses on the present understanding in IL-18 and its potential role in acute pancreatitis. IL-18 levels reflect the severity of acute pancreatitis and display a significant negative correlation with the concentrations of antioxidative damage factors, serum selenium and glutathione peroxidases (GPx). The relationship between IL-18 and other pro-inflammatory cytokines shows that IL-18 is one of the key mediators of inflammation in the pathogenesis of acute pancreatitis. Elevation of serum IL-18 levels may mediate acute pancreatitis associated liver injury. The use of IL-18 antagonists as direct routes to block IL-18 activity and P2X7 receptor antagonists and interleukin-1beta-converting enzyme (ICE) inhibitors as indirect routes to block IL-18 activity suggest that specific therapeutic inhibition of IL-18 is a promising therapeutic approach for acute pancreatitis.