A general method has been developed for the expedient solid-phase synthesis of aspartyl protease inhibitors that do not incorporate any amino acids. The synthesis approach was designed to allow the introduction of diverse functionality at all four variable sites in inhibitors 1a,b using readily available precursors. Representative, analytically pure inhibitors were obtained in 45-64% overall yields for the 12-step solid-phase synthesis sequence that includes both stereoselective reduction and carbon-carbon bond forming steps. A Library of 204 spatially separate compounds was also prepared and screened against cathepsin D and resulted in the identification of a number of potent small molecule inhibitors (K-i = 0.7-3 nM). The described synthesis approach enables the rapid identification of small molecule inhibitors to diverse aspartyl protease targets. The general design principles are also applicable to other enzyme classes.