The process of tumor progression and metastasis involves degradation of the extracellular matrix and is governed by an intricate balance of proteases, their activators and their inhibitors, in which malignant cells are permitted to infiltrate the adjacent structures and gain access to lymph and blood vessels. These proteases can be broadly categorized into three families: matrix metalloproteinases, serine proteinases and cysteine proteinases, all of which have all been implicated in these processes. The presence of neural invasion is often considered to be a poor prognostic sign; however, the cellular mechanisms underlying this propensity for perineural invasion are unknown. We recently researched the relationship between the glial cell line-derived neurotrophic factor and perineural invasion by human pancreatic cancer cells. We also confirmed that NF-kappa B is a part of the signaling pathway from the glial cell line-derived neurotrophic factor in human pancreatic cancer cells, and documented the inhibitory effect of gabexate mesilate, a well-known non-physiological synthetic serine protease inhibitor, for pancreatic cancer invasion. Recent studies on the role of proteases and protease inhibitors in pancreatic cancer invasion are also reviewed.