Salinity stress occurs when salt concentration in the environment changes rapidly, for example because of tidal water flow, rainstorms, drought, or evaporation from small bodies of water. However, gradual changes in salt concentration can also cause osmotic stress in aquatic habitats if levels breach thresholds that reduce the fitness of resident organisms. The latter scenario is exemplified by climate change driven salinization of estuaries and by dilution of ocean surface salinity through changes in the water cycle. In this review, we discuss how fish employ the evolutionarily conserved cellular stress response (CSR) to cope with these different forms of salinity stress. Macromolecular damage is identified as the cause of impaired physiological performance during salinity stress and serves as the signal for inducing a CSR. Basic aspects of the CSR have been observed in fish exposed to salinity stress, including repair and protection of cellular macromolecules, reallocation of energy, cell cycle arrest, and in severe cases, programmed cell death. Osmosensing and signal transduction events that regulate these aspects of the CSR provide a link between environmental salinity and adaptive physiological change required for survival. The CSR has evolved to broaden the range of salinities tolerated by certain euryhaline fish species, but is constrained in stenohaline species that are sensitive to changes in environmental salinity. Knowledge of how the CSR diverges between euryhaline and stenohaline fish enables understanding of physiological mechanisms that underlie salt tolerance and facilitates predictions as to the relative vulnerabilities of different fish species to a rapidly changing hydrosphere.