The relationship between Ca2+ and lens fiber cell communication was investigated in the isolated intact rat lens by using radiotracer and electrophysiological techniques. The lens internal calcium was increased by adding the SH oxidant diamide (1 mM), by incubating in a sodium-free (n-methylglucamine/ solution or by increasing external calcium from 1 to 10 mM. A 12 hours incubation in diamide produced a ten-fold increase in 45Ca uptake into the lens which was accompanied by a ten-fold increase in internal resistance. Incubation in Na-free solution or in 10 mM Ca2+ both produced a 5-fold increase in 45Ca content, while the increase in internal resistance was five and six fold respectively. This uncoupling was prevented in the diamide and Na-free treated lenses by omitting Ca2+ from the incubation medium.Fiber cell uncoupling was noticed in each of these experimental conditions after approximately 5 hours incubation, and good recovery was obtained in the high calcium solution if the stress was removed.The calmodulin antagonists calmidazolium (3μM) and W7 (100μM) both prevented uncoupling in the high calcium solution, provided there was a 2 hours preincubation period in calcium-free solution containing antagonist before the stress was applied.These data indicate that lens fiber cell communication is regulated by Ca2+ and calmodulin.