The caudal neurosecretory system (CNSS) is a fish-specific neuroendocrine complex whose function(s) remain uncertain despite over 60 years of research. Osmoregulatory roles for the CNSS have been hypothesized, but molecular regulation of the CNSS following changes in environmental salinity remains poorly characterized. Therefore, we performed transcriptomics on the CNSS of rainbow trout (Oncorhynchus mykiss) to establish: (1) how the CNSS responds following seawater (SW) transfer, and (2) which endocrine systems contribute to osmoregulatory responses in the CNSS. Responses following SW transfer varied at 24 h versus 168 h, with changes primarily affecting membrane transport and transcriptional processes at 24 h and neuronal processes at 168 h. Components of several osmoregulation-associated endocrine systems were affected (e.g., corticosteroid receptors), including some that have not previously been identified in the CNSS (e.g., calcitonin). Additionally, transcript levels of corticotropin-releasing factor (CRF) peptides-which have osmoregulatory functions and were highly abundant in the CNSS-were approximately twofold higher after 24 h in SW. Therefore, we performed additional experiments investigating CRF peptides in a more euryhaline salmonid, Atlantic salmon (Salmo salar). Smolts had up to 12-fold higher levels of CRF peptide transcripts than parr, but abundance declined following SW transfer. Additionally, CRF transcripts were lower 24 h following freshwater transfer of SW-acclimated salmon. These results suggest that CRF peptides acutely aid in coordinating physiological responses following fluctuations in environmental salinity via anticipatory and/or responsive mechanisms. Collectively, our data indicate that CNSS-mediated production of CRF peptides has osmoregulatory functions and provide a resource for investigations of novel CNSS functions.