SUMMARY The salinity tolerance of the `California' Mozambique tilapia( Oreochromis mossambicus × O. urolepis hornorum ), a current inhabitant of the hypersaline Salton Sea in California, USA, was investigated to identify osmoregulatory stress indicators for possible use in developing a model of salinity tolerance. Seawater-acclimated (35 g l –1 ) tilapia hybrids were exposed to salinities from 35–95 g l –1 , using gradual and direct transfer protocols, and physiological (plasma osmolality, [Na + ],[Cl – ], oxygen consumption, drinking rate, hematocrit, mean cell hemoglobin concentration, and muscle water content), biochemical(Na + , K + -ATPase) and morphological (number of mature,accessory, immature and apoptotic chloride cells) indicators of osmoregulatory stress were measured. Tilapia tolerated salinities ranging from 35 g l –1 to 65 g l –1 with little or no change in osmoregulatory status; however, in fish exposed to 75–95 g l –1 salinity, plasma osmolality, [Na + ],[Cl – ], Na + , K + -ATPase, and the number of apoptotic chloride cells, all showed increases. The increase in apoptotic chloride cells at salinities greater than 55 g l –1 , prior to changes in physiological and biochemical parameters, indicates that it may be the most sensitive indicator of osmoregulatory stress. Oxygen consumption decreased with salinity, indicating a reduction in activity level at high salinity. Finally, `California' Mozambique tilapia have a salinity tolerance similar to that of pure Mozambique tilapia; however, cellular necrosis at 95 g l –1 indicates they may be unable to withstand extreme salinities for extended periods of time.