Publisher Summary Serine integral membrane peptidases (SIMP), including DPPIV, seprase, and related prolyl peptidases, which are both Pro-Xaa cleaving enzymes and adhesion molecules, are likely to emerge as an important protease family. The main functions of SIMPs reside in their proteolytic and adhesive capacities, thus influencing cellular activities, migration, and invasion. These membrane proteases may form a physically and functionally linked complex at invadopodia during cellular invasion. The cysteine-rich domain of some peptidases exhibits the capability of binding to multiple molecules. This could allow not only activation of the peptidases themselves but also association with other membrane proteases to participate in cooperative extracellular matrix (ECM) protein degradation at invadopodia during cancer invasion. This chapter focuses on a small group of membrane serine peptidases, the SIMP, that are inducible, specific for proline-containing peptides and macromolecules, and active on the cell surface. Prototypes of SIMP members are DPPIV and seprase. Other SIMP-related peptidases, including quiescent cell proline aminodipeptidase (QPP), prolyl carboxy-peptidase (PCP), prolyl endopeptidase (PEP), dipeptidyl peptidase 6 (DPP6), dipeptidyl peptidase 8 (DPP8), dipeptidyl peptidase 9 (DDP9), attractin, dipeptidyl peptidase II (DPPII), and dipeptidyl peptidase IV-β (DPPIV-β), have subtle structural and functional differences from DPPIV and seprase, and they are also discussed in the chapter.