Cyclic ADP-ribose (cADPR) is a newly identified nucleotide1,2 which can release calcium from a variety of cells3-6, suggesting it is a messenger for mobilizing internal Ca2+ stores. Its cyclic structure has now been confirmed by X-ray crystallography7. Available results are consistent with it being a modulator of Ca2+ -induced Ca2+ release8-10. Here we report that sea urchin egg microsomes purified by Percoll gradients lose sensitivity to cADPR, but the response can be restored by a soluble protein in the supernatant. Purification and characterization of the protein indicate that it is calmodulin. It appears to be sensitizing the Ca2+ release mechanism because caffeine and strontium, agonists of Ca2+ -induced Ca2+ release, can also mimic calmodulin in conferring cADPR-sensitivity. Although evidence indicates that cADPR may be an activator of the ryanodine receptor 8-10, present results point to the importance of accessory proteins such as calmodulin in modulating its activity.