Memapsin 2 (β-secretase, BACE 1) processing of β-amyloid precursor protein is the first step in the pathway leading to the production of amyloid-β, thus, it is a major target for the development of inhibitor drug for the treatment of Alzheimerss Disease. Although there are distinctive advantages of this protease as a drug target, the development of drug-like memapsin 2 inhibitors has been somewhat slow since the cloning of the protease seven years ago. Here we review the progress of memapsin 2 inhibitor development using crystal structure-based design cycles. Recent progress has evolved the inhibitors into sizes sufficiently small to penetrate cell membranes and the blood-brain barrier yet retain potency for the inhibition of Aβ production in cultured cells and experimental animals. Such progress lends optimism that clinically useful memapsin 2 inhibitors will eventually be developed.