Amyloid fibrils are filamentous, β-sheet-rich protein aggregates implicated in numerous neurodegenerative diseases, including Alzheimer's, Huntington's, Parkinson's, and Cerebral Amyloid Angiopathy. Fibrils share a common molecular architecture called a cross-β structure, where the β-strands are oriented perpendicular to the growth axis of the β-sheets. Fibrils can be comprised of either parallel or antiparallel β-sheets, but share a cross-β structure characterized by inter-strand and sheet spacings between 4 -5 Å and 8 -12 Å, respectively. Despite sharing this common structural motif, amyloids exhibit structural polymorphism, meaning that the same peptide or protein can aggregate to form fibrils with different structures. These structural variations can arise from different packing arrangements of protofilament segments or being comprised of structurally distinct cross-β subunits. Mounting evidence from biophysical studies, cell toxicity assays, transgenic mice models, and human tissue indicate that structural polymorphism influences the biological activities of fibrils and may be linked to different pathological phenotypes in human diseases. Consequently, there has been intense interest in developing tools to characterize structures of fibril polymorphs, as well as the interactions that stabilize them and promote their formation.