Although long recognized in microvascular research, an increasing body of evidence suggests that inflammatory markers are present in human diseases. Since the inflammatory cascade serves as a repair mechanism, the presence of inflammatory markers in patient groups has raised an important question about the mechanisms that initiate the inflammatory cascade (i.e., the mechanisms that cause tissue injury). Using a severe form of inflammation, shock, and multiorgan failure, for which there is no accepted injury mechanism, we summarize studies that suggest that the powerful pancreatic digestive enzymes play a central role in the destruction of the intestine and other tissues if their compartmentalization in the lumen of the intestine and in the pancreas is compromised. Further, we summarize evidence that uncontrolled degrading enzyme activity in plasma causes proteolytic cleavage of the extracellular domain of membrane receptors and loss of associated cell functions. For example, in a model of metabolic disease with type II diabetes, proteolytic cleavage of the insulin receptor causes the inability of insulin to signal glucose transport across membranes. The evidence suggests that uncontrolled proteolytic and lipolytic enzyme activity may trigger the mechanism for tissue injury. The significance of such mechanisms remain to be explored in human diseases.