Biomarkers are essential for performing early diagnosis, monitoring neurodegenerative disease progression, gauging responses to therapies, and stratifying neurodegenerative diseases into their different subtypes. A wide range of molecular markers are under investigation in tissues and biofluids as well as through imaging; moreover, many are prominent proteins present in cerebrospinal fluid. However, in more frequently and easily collected fluids such as plasma, these proteins show only a modest correlation with disease and thus lack the necessary sensitivity or specificity for clinical use. High-throughput and quantitative proteomic technologies and systems-driven approaches to biofluid analysis are now being utilized in the search for better biomarkers. Biomarker discovery involves many critical steps including study design, sample preparation, protein and peptide separation and identification, and bioinformatics and data integration issues that must be carefully controlled before independent confirmation and validation. In this review, we summarize current proteomic and nucleic acid technologies involved in the discovery of biomarkers of neurodegenerative diseases, particularly Alzheimer's, Parkinson's, Huntington's, and prion diseases.