Incorporation of traditional aspartyl protease transition-state isosteres such as statines and hydroxyethylamines into peptidomimetic scaffolds has resulted in the discovery of potent BACE inhibitors. Their therapeutic use to treat Alzheimer's disease has, however, been limited by the challenge of combining potency and adequate physical properties of such inhibitors to permeate the CNS. The discovery of a novel aspartyl protease binding motif and its incorporation into potent BACE inhibitors displaying improved physical properties will be presented. The binding of this motif in the catalytic site of BACE and its impact on the enzyme's topology will be described and illustrated by several crystal structures.