Background : Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States. Its lethality is due, in large part, to its resistance to traditional chemotherapeutics. As a result, there is an enormous effort being put into basic research to identify proteins that are required for PDA progression so that they may be specifically targeted for therapy. Objective : To compile and analyze the evidence that suggests that extracellular proteases are significant contributors to PDA progression. Methods : We focus on three different extracellular protease subclasses expressed in PDA: metalloproteases, serine proteases and cathepsins. Based on data from PDA and other cancers, we suggest their probable roles in PDA. Results/conclusions : Of the proteases expressed in PDA, many appear to have overlapping functions, based on the substrates they process, making therapeutics complicated. Two protease families most likely to have unique, critical functions during tumor progression, and therefore strong potential as therapeutic targets, are the a disintegrin and metalloproteases (ADAMs) and the cathepsins.