The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic- or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstream induction of T cells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.