Assessing human cerebrospinal fluid (CSF) provides a practical way to conduct longitudinal molecular analyses of changes during the course of neurological disease. Integrated and parallel analyses of neurotransmitters, neuropeptides and proteins in CSF may reveal better insights into complex interaction of numerous cell types in the central nervous system (CNS) at an unprecedented level of complexity and detail. Intricate molecular fingerprints of CSF proteins may pinpoint multiple underlying pathogenic mechanisms as well as an acute and a chronic CNS disease component. Some of these changes may be mapped to altered protein expression patterns in clinically relevant cell populations with a causative or diagnostic disease link. A CNS proteome database of primary human CNS tissues may avoid ambiguities of experimental models and accelerate pre- and clinical development of more specific diagnostic and prognostic disease markers and new selective therapeutics.