We have been involved in the development and use of realistic computer simulations of proteins to characterize the conformational changes associated with amyloid formation. In so doing we discovered a novel structure adopted by amyloidogenic proteins, but not ‘normal’ proteins, and we proposed that it defines the toxic soluble oligomers formed en route to the nontoxic mature fibrils. As such, this structure, which we call α-sheet, represents a new target for amyloid therapeutics and diagnostics. We have designed, synthesized, and tested compounds to be complementary to this ‘toxic’ structure and they inhibit amyloid formation of Aβ (Alzheimer’s Disease), transthyretin (systemic amyloid disease and heart disease), and amylin (type 2 diabetes), as well as several biofilmforming bacteria, by specifically binding the toxic oligomers, which in turn neutralizes the toxic species. These α-sheet compounds represent a novel platform for attacking these diseases and the hope of disease-modifying treatments and early diagnosis.