The functional role of secretin outside the gastrointestinal system has been a mystery to endocrinologists for many years. With the availability of secretin- and secretin receptor-knockout models and the advances of electrophysiological and immunohistochemical techniques, we are now in a good position to explore the functions of secretin outside the gastrointestinal system. There is growing evidence to support that secretin works pleiotropically at multiple levels in our body. In this paper, we review the recent findings regarding the physiological effects of secretin on extragastrointestinal sites including the cerebellum, the hippocampus, and the hypothalamus-pituitary-kidney axis. To understand the mechanisms underlying the site-specific expression of secretin and secretin receptors in the central nervous system, we also discuss the transcriptional regulation of secretin and secretin receptor genes in neuronal cell lines. © 2011 New York Academy of Sciences.