MFG‐E8 was initially identified as a principle component of the Milk Fat Globule, a membrane‐encased collection of proteins and triglycerides that bud from the apical surface of mammary epithelia during lactation. It has since been independently identified in many species and by many investigators and given a variety of names, including p47, lactadherin, rAGS, PAS6/7, and BA‐46. The acronym SED1 was proposed to bring cohesion to this nomenclature based upon it being a Secreted protein that contains two distinct functional domains: an N‐terminal domain with two EGF‐repeats, the second of which has an integrin‐binding RGD motif, and a C‐terminal domain with two Discoidin/F5/8C domains that bind to anionic phospholipids and/or extracellular matrices. SED1/MFG‐E8 is now known to participate in a wide variety of cellular interactions, including phagocytosis of apoptotic lymphocytes and other apoptotic cells, adhesion between sperm and the egg coat, repair of intestinal mucosa, mammary gland branching morphogenesis, angiogenesis, among others. This article will explore the various roles proposed for SED1/MFG‐E8, as well as its provocative therapeutic potential. J. Cell. Biochem. 106: 957–966, 2009. © 2009 Wiley‐Liss, Inc.