The β-secretase-mediated generation of amyloid-β peptide (Aβ) is involved in the pathogenesis of Alzheimer's disease. This paper describes the characterization of the first orally available non-peptidic β-secretase inhibitor, LY2811376. The β-secretase 1 (BACE1) inhibitor, which was identified by fragment-based screening, lowered Aβ levels in a mouse model of Alzheimer's disease as well as in normal dogs. In healthy volunteers LY2811376 was safe and well tolerated and produced long-lasting reductions in Aβ levels. Although the authors note that non-target-related toxicology prevented the compound from progressing to clinical development, this study shows that BACE1 is a tractable target in humans.