ABSTRACT: The adamalysins are a family of proteins in the metzincin super-family of metalloproteases, which also includes the matrix metalloproteinases. There are two subfamilies of adamalysins: the snake venom metalloproteases (SVMPs) and the ADAMs (proteins containing a disintegrin and metalloprotease domain). At least 23 ADAMs have been identified to date. The ADAMs are expressed by a wide variety of cell types, and are involved in functions as diverse as sperm-egg binding, myotube formation, neurogenesis, and proteolytic processing of cell surface proteins. An overview of the ADAM family and their functions will be presented. TACE is a unique member of the ADAM family that cleaves membrane-bound TNF-α to generate soluble TNF-α. Mice lacking proteolytically active TACE have been generated and characterized. The TACE knock-out results in perinatal lethality. Cells from the TACE-deficient mice release 80-90% less soluble TNF-α than do wild-type cells. Irradiated mice that are reconstituted with TACE knock-out hematopoeitic stem cells have markedly reduced levels of serum TNF-α following LPS challenge, compared to irradiated mice reconstituted with wild-type cells, suggesting that TACE is the major TNF-α converting enzyme in vivo. TACE-deficient cells are compromised in the generation of other soluble proteins that are produced as the result of cleavage of a membrane precursor form, suggesting that TACE is involved in multiple shedding events.