Few macromolecules have become the object of more intense chemical and biological scrutiny in recent years than has the l3-amyloid precursor protein. This highly conserved and widely expressed integral membrane protein is the focus of a rapidly growing number of studies aimed at its characterization by protein chemical, molecular biological, cell biological, and neuroanatomical methods. The principal reason for this attention is clear. The early promise that a 39-43 residue fragment of I3APP, the amyloid l3-protein (AI3), might play a central role in the pathogenesis of Alzheimer's disease has increasingly been borne out. Although there is still substantial debate about exactly when AI3 becomes involved in Alzheimer's disease and how attractive a therapeutic target it represents, accumulating evidence now points to an early and sometimes causative role in the pathogenetic cascade. I3APP has become a compelling example of the phenomenon of research that begins with a strictly disease-oriented focus giving rise to novel insights about the normal biology of a whole family of macromolecules, in this case about the processing of certain cell surface, single membrane-spanning polypeptides. Here, I review recent information about the normal structure and function of I3APP and how its AI3 fragment contributes to Alzheimer's disease. Such