Pericellular proteases can degrade extracellular matrix proteins and reshape their microenvironment, as well as cleave and activate signaling molecules such as growth factors and their receptors. In this capacity, pericellular proteolysis is essential for multiple biological processes, including development, tissue homeostasis and tissue repair. On the flip side, dysregulated pericellular proteolysis is a hallmark in many pathological conditions including cancer, and is believed to be critically involved in tumor growth, invasion and dissemination of cancer cells to other organs. Matriptase is a member of the family of Type II transmembrane serine proteases, and has been implicated in a variety of epithelial cancers. This review summarizes current knowledge about matriptase and its role in cancer based on expression studies, biochemical characterization, cell-culture based studies and in vivo experiments.