Amyloid fibrils are insoluble, non-crystalline protein aggregates that are commonly associated with many diseases, such as Alzheimer's Disease (AD), Cerebral Amyloid Angiopathy (CAA), and Type II Diabetes. Amyloid fibrils exhibit structural polymorphism, which can influence their toxicity, how they grow, and propagate. Investigating how different fibril polymorphs aberrantly interact with their local biological environment is critical to understanding the clinical variations of diseases observed in patients. Unfortunately, investigating this is challenging, as there is a lack of biophysical methods to monitor the structure and dynamics of fibrils in their native biological environments. Here, we discuss our group’s work in addressing this problem. We are developing characterization methods using Raman microscopy to quantitatively assess the molecular-level structure of fibrils. For example, we recently developed methods to measure important dihedral and bond orientation angles in fibrils. To determine the molecular-level structure of different polymorphs, we use these angular measurements as experimental constraints in molecular dynamics simulations. The resulting simulations from the production runs yield an ensemble of structures that are consistent with the experimental Raman data. We are working towards translating some of our methodologies towards Raman imaging applications to quantitively assess amyloid fibril structures found in plaques from brain tissue of AD and CAA patients.