Biology in its broadest sense is a multifaceted endeavor aimed at solving a puzzle with a finite, but extremely large, number of pieces. Often it is hard to predict how wide the gap separating two individual bits of knowledge within the larger picture would be. Therefore, when researchers working in diverse fields simultaneously realize that their fragments of the puzzle fit together, what appeared as an insurmountable distance is bridged rapidly as the remaining pieces are fitted into place. Several studies published recently by developmental biologists, neuroscientists, and researchers who are interested in the identification of therapeutic targets and treatments for Alzheimer’s disease (AD) have tied together diverse phenomena into one coherent paradigm. As a result, a new signal transduction paradigm has emerged (Brown et al. 2000; Mumm et al. 2000) that is shared by Notch, lipid-sensing mechanisms in the cell, possibly the unfolded protein response (UPR), and a proteolytic pathway that is central to the pathogenesis of AD. The culmination of these observations is four papers that were published this summer that provide compelling evidence for the existence of a novel class of enzymes (Esler et al. 2000; Li et al. 2000a, b; Seiffert et al. 2000). These enzymes are polytopic membrane proteins that are capable of catalyzing the intramembranous hydrolysis of a peptide bond. The founding members of this class of proteases are the presenilin proteins (PS).