The initial injury in acute pancreatitis is characteristically sterile and results in acinar cells necrosis. Intracellular contents released from damaged cells into the extracellular space serve as damage-associated molecular patterns (DAMPs) that trigger inflammation. There is increasing evidence that this sterile inflammatory response mediated through DAMPs released from necrotic acinar cells is a key determinant of further pancreatic injury, remote organ injury, and disease resolution in experimental models. A number of DAMPS, including high-mobility group box protein 1, DNA, adenosine triphosphate and heat shock protein 70, have been shown to have a role in experimental pancreatitis. Many of these DAMPs are also detectable in the human pancreatitis. Genetic deletion and pharmacologic antagonism demonstrate that specific DAMP receptors, including Toll-like receptor (TLR) 4, TLR9, and P2X7, are also required for inflammation in experimental acute pancreatitis. Downstream DAMP-sensing components include nod-like receptor protein 3, caspase 1, interleukin-1β (IL-1), IL-18, and IL-1 receptor, and also are required for full experimental pancreatitis. These DAMP-mediated pathways provide novel therapeutic targets using antagonists of TLRs and other receptors.