In their aqueous habitats, fish are exposed to a wide range of osmotic conditions and differ in their abilities to respond adaptively to these variations in salinity. Fish species that inhabit environments characterized by significant salinity fluctuation (intertidal zone, estuaries, salt lakes, etc.) are euryhaline and able to adapt to osmotic stress. Adaptive and acclimatory responses of fish to salinity stress are based on efficient mechanisms of osmosensing and osmotic stress signaling. Multiple osmosensors, including calcium sensing receptor likely act in concert to convey information about osmolality changes to downstream signaling and effector mechanisms. The osmosensory signal transduction network in fishes is complex and includes calcium, mitogen-activated protein kinase, 14-3-3 and macromolecular damage activated signaling pathways. This network controls, among other targets, osmosensitive transcription factors such as tonicity response element binding protein and osmotic stress transcription factor 1, which, in turn, regulate the expression of genes involved in osmotic stress acclimation. In addition to intracellular signaling mechanisms, the systemic response to osmotic stress in euryhaline fish is coordinated via hormone- and paracrine factor-mediated extracellular signaling. Overall, current insight into osmosensing and osmotic stress-induced signal transduction in fishes is limited. However, euryhaline fish species represent excellent models for answering critical emerging questions in this field and for elucidating the underlying molecular mechanisms of osmosensory signal transduction.