Many membrane-bound receptors, growth factors, and ligands are proteolytically processed in or near the membrane. The release of these proteins from vesicles, organelles or the cell surface is accomplished by the sequential action of membrane-tethered sheddases and membrane-embedded proteases in a process known as regulated intramembrane proteolysis or RIP. Many sheddases are members of the A Disintegrin And Metalloproteinase (ADAM) family, including ADAM17 (TNF-alpha converting enzyme or TACE), the meltrins, and ADAM10 (also known as Kuz). Other sheddases of biological and biomedical importance include the aspartyl proteases beta-secretase (BACE1) and its homolog BACE2. Upon release of ectodomains by sheddases, the membrane-bound remnants are often cleaved by membrane-embedded proteases, which include the presenilin-containing gamma-secretases and the SPP, Rhomboid and S2P families. These proteases contain multiple transmembrane domains, and their active sites reside within the boundaries of the lipid bilayer. Proteolysis within the transmembrane region of the substrate leads to release of the cytoplasmic domain, which in some cases can translocate to the nucleus and regulate transcription. Dysregulation of RIP proteases, either the membrane-tethered sheddases or the membrane-embedded proteases, can lead to diseases such as Alzheimer’s, cancer, allergies, obesity, cardiac hypertrophy, and autoimmune diseases, and many of these enzymes are targets for potential therapeutic intervention. This conference will focus on the processes and proteases involved in the regulated proteolysis of cell surface proteins as they relate to biology and medicine.