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Cyclic ADP-ribose (cADPR), an endogenous modulator of ryanodine receptor Ca²⁺-releasing channels, is found in various tissues. Cytosolic injection of cADPR induces an elevation of intracellular Ca²⁺ concentrations or potentiates Ca²⁺ increases. cADPR facilitates neurotransmitter or insulin release and modifies ionic currents. cADPR is synthesized by ADP-ribosyl cyclase and is metabolized by cADPR hydrolase. ADP-ribosyl cyclase activity is up-regulated by nitric oxide/cyclic GMP-dependent phosphorylation or receptor stimulation via G-proteins within membranes. These findings suggest that cADPR is a second messenger in cellular Ca²⁺ signaling. However, many intriguing issues remain to be addressed before this identity is confirmed.