Amyloid assemblies are found in many neurodegenerative pathologies including Alzheimer’s, Huntington’s, and prion diseases. Although much is known about the physiological consequences of these assemblies, very little is known about the high resolution structures of these b-sheet rich fibrils and their oligomeric precursors. A combination of several biophysical methodologies including solid-state NMR, infrared spectroscopy, fluorescence assays, electron microscopy, and atomic force microscopy are being used to obtain high resolution structural information of these multimeric complexes. The data obtained is being used to design novel peptide and small molecule inhibitors to disrupt the formation of these assemblies and reduce their toxicity to cultured neurons.