Global characterisation of proteins and the comparison between proteomes is providing new insights into general biological structures and processes, as well as between physiological and pathological conditions. During both embryonic development and adult life, brain cavities and ventricles are filled with a complex protein-rich fluid, the cerebrospinal fluid (CSF). In the last few years, it has been suggested that adult CSF has a key function as a fluid pathway for delivering diffusible signals to the brain, thus affecting the behaviour of specific brain parenchyma cells, particularly the putative neural stem cells. Accordingly, some pathologies that affect the central nervous system (CNS), such as neurodegenerative diseases and/or neurological disorders, are reflected in CSF protein content, either as a cause or as a consequence. Adult CSF is considered to be the successor of embryonic CSF (E-CSF). Most of the proteins contained within E-CSF, as analysed in avians (chick) and mammals (rat and human), are also detected in adult humans, suggesting that some of their roles in CNS cell behaviour are similar. Despite the heterogeneity of the currently available data, which is due to technical differences in the proteomic analyses, the use of different model systems and the great variety of sample sources, it is increasingly clear that this fluid regulates the behaviour of neural stem cells throughout development and during adult life, thus suggesting a possible approach to brain cell therapies. This review focuses on current data regarding CSF proteomes in relation to CSF functions in both physiological and pathological conditions, as well as on CSF manufacture.