The technology, experimental approaches, and bioinformatics that support proteomic research are evolving rapidly. The application of these new capabilities to the study of neurodegenerative diseases is providing insight into the biochemical pathogenesis of neurodegeneration as well as fueling major efforts in biomarker discovery. Here, we review the fundamentals of commonly used proteomic approaches and the outcomes of these investigations with autopsy and cerebrospinal fluid samples from patients with neurodegenerative diseases.