It is believed that the production and accumulation of beta-amyloid (Abeta) peptide is a critical step to the pathogenesis of Alzheimer's disease (AD). BACE 1 (beta-site APP-cleaving enzyme 1 or beta-secretase), the key enzyme required for generating Abeta from the beta-amyloid precursor protein (APP), is regarded as an ideal target for AD therapeutic drug design. Due to low oral bioavailability, metabolic instability and poor ability to penetrate the central nervous system (CNS) of the existing peptidomimetic inhibitors, researchers have paid more attention to the development of nonpeptidomimetic inhibitors in recent years. A number of drug screening approaches and technologies have been used to identify novel nonpeptidomimetic BACE 1 inhibitors. This review mainly focuses on the recent developments in structure-based design and synthesis of the nonpeptidomimetic BACE 1 inhibitors.