Proteolysis on the cell surface and in the extracellular matrix is essential for normal cellular functions during development and in the adult, but it may also have undesirable consequences, such as promoting cancer, arthritis, and Alzheimer's disease. Recent advances highlight the roles of zinc-dependent metalloproteinases (metzincins) in proper skeletal development, in activating EGF-receptor ligands, in Notch-dependent signaling, and in initiating and promoting tumorigenesis.