Large mammal models are unique in that it is possible to analyse the real-time release of neural factors over several hours or even days in a conscious unstressed state. Until recently, hypophyseal portal blood sampling was the only reliable method available for this purpose. However, development of an alternative approach, in which cerebrospinal fluid (CSF) is collected from specific sites within the cerebroventricular system, has provided another route by which hypothalamic activity can be investigated. Use of this approach, in combination with other methods, such as intracerebroventricular infusion or simultaneous hypophyseal portal blood collection, has yielded exciting novel data that challenge long-held dogma on the pathways of communication in the brain. It is clear that factors in the CSF are released site-specifically and, thus, this fluid is not homogeneous; the concentration of a factor in lumbar CSF may bear no relation to its ventricular concentration. Data also indicate that there is little, if any, transfer of factors between the CSF and the hypophyseal portal system. In addition, there is mounting evidence indicating that factors in CSF may serve as part of a non-synaptic communication system in the brain. Establishing an unequivocal function for CSF-borne factors may prove technically difficult, if not impossible. However, we believe that there is strong evidence supporting a role for one such factor, GnRH in CSF, in sexual behaviour.