The determination of the three-dimensional X-ray crystal structure of b-secretase (BACE) complexed with an inhibitor has greatly facilitated the design of BACE inhibitors. Generally, BACE inhibitors can be grouped into two main families: substrate-based inhibitors designed as peptidomimetic inhibitors and nonpeptidomimetic inhibitors. This review focuses on the rational design of inhibitors based on transition-state analogues. The structural nature of peptidomimetic inhibitors usually implies relatively poor catabolic stability and low bioavailability after systemic administration due to low blood-brain barrier permeability. To overcome these drawbacks, several different approaches have been used.