β-Secretase (BACE-1), a key enzyme in the etiopathogenesis and progression of Alzheimer Disease, is the focus of medicinal chemistry efforts both in the pharmaceutical industry and in academia. Despite the availability of diverse peptidomimetic BACE-1 inhibitors, nonpeptidic compounds suitable for oral delivery and transport across the blood brain barrier are in great demand. Herein, a number of active and structurally diverse inhibitors were selected and subjected to an ensemble-docking process into five BACE-1 X-ray structures. The calculated bioactive conformations of these inhibitors allowed us to build an exhaustive pharmacophore model, which captures both the common geometric and electronic features essential for enzyme inhibition. The model is intended to aid the rational design of new BACE-1 inhibitors. Furthermore, a comparison of BACE/cathepsin D X-ray structures was made to provide guidelines for the design of BACE-selective inhibitors.