A group of type II integral serine proteases, including dipeptidyl peptidase IV (DPP4/CD26), seprase/fibroblast activation protein α (FAPα) and related type II transmembrane prolyl serine peptidases, exert their mechanisms of action on the cell surface. DPP4 and seprase exhibit multiple functions due to their abilities to form complexes with each other and to interact with other membrane-associated molecules. Localization of the protease complexes at cell surface protrusions, called invadopodia, may have a prominent role in processing soluble factors (including chemokines and neuropeptide Y) and in degrading locally extracellular matrix components, that are essential to the cell migration and matrix invasion occurring during tumor invasion, angiogenesis and metastasis.