Neurodegenerative diseases are characterized by the malfunction and/or death of nerve cells, i.e. neurons, in the central and peripheral nervous system. Many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and the prion diseases, involve the misfolding and aggregation of naturally occurring proteins. These aggregates are thought to be toxic to cells, playing a critical role in neurodegeneration. This chapter focuses on how FTIR spectroscopy and microspectroscopy have been used to evaluate the structural changes in these disease-related proteins. It also examines the effects of lipid peroxidation and breakdown, and the disease-related metabolic changes in carbohydrate and nucleic acid composition. Methods for examining these biochemical changes in vitro, in cell culture, and in tissue are described. Finally, recent applications to a wide range of neurodegenerative diseases will be profiled with an outlook toward future advances and uses of FTIR spectroscopic methods for understanding, diagnosing, and treating neurodegenerative diseases.