Cyclic adenosine diphosphate-ribose, an endogenous metabolite of nicotinamide adenine dinucleotide was first characterized as a potent Ca2+ mobilizing agent in sea urchin eggs. Mounting evidence points to it being an endogenous activator of Ca(2+)-induced Ca2+ release by non-skeletal muscle ryanodine receptors in several invertebrate and mammalian cell types. Cyclic adenosine diphosphate-ribose is synthesized by adenosine diphosphate-ribosyl cyclases, which have been found to be widespread enzymes. Recent data suggests that cyclic adenosine diphosphate-ribose may function as a second messenger in sea urchin eggs at fertilization and in stimulus secretion coupling in pancreatic beta-cells. A second messenger role for cyclic adenosine diphosphate-ribose requires that its intracellular levels be under the control of extracellular stimuli. Another second messenger, cGMP, stimulates the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide by activating the adenosine diphosphate-ribosyl cyclase pathway in sera urchin eggs and egg homogenates, suggesting that cyclic adenosine diphosphate-ribose may be an intracellular messenger for cell surface receptors or nitric oxide, which activate cGMP-producing guanylate cyclases. Cyclic adenosine diphosphate-ribose may have a similar role to inositol trisphosphate in controlling intracellular calcium signalling with these two calcium-mobilizing second messengers activating ryanodine receptors and inositol trisphosphate receptors respectively.