The clinical diagnosis of major neurodegenerative disorders, e.g. Alzheimer's disease, Parkinson's disease, and dementia with Lewy body, remains unsatisfactory based on current clinical criteria and limited laboratory investigations. The possibility of identifying multiple novel biomarkers for neurodegenerative diseases, those related to disease pathogeneses in particular, has been greatly enhanced with recent advances in genomics, proteomics, and metabolomics. In this chapter, we will be reviewing a few issues related to proteomic identification of proteins in human cerebrospinal fluid (CSF) as well as unique protein markers that could be used for clinical diagnosis of various neurodegenerative diseases or monitoring their progression. Great attention has been directed to practical considerations and limitations of several major aspects of proteomic analysis of human CSF.