CD38, a multifunctional enzyme, generates two potent Ca2+-releasing signal metabolites, cyclic ADP-ribose (cADPR) and NAADP+, thereby upmodulating many important Ca2+-mediated cell functions. A topological paradox has long been recognized, as CD38 is an ectoenzyme, or an intravesicularly located enzyme in subcellular membrane vesicles, therefore apparently shielded from its substrate NAD+. Moreover, cADPR generated by CD38 should be unavailable to its target Ca2+ stores, the ryanodine receptors (RyR). We have solved this paradox by identifying some NAD+ and cADPR transmembrane transporters, whose interplay mediates a hitherto-unrecognized subcellular and intercellular trafficking of nucleotides that enhances intracellular Ca2+ ([Ca2+]i). Connexin 43 (Cx43) hemichannels mediate an equilibrative transport of NAD+ from the cytosol to the active site of CD38 (either ectocellular or intravesicular). Subsequent translocation of in situ-generated cADPR to reach the RyR is performed, (i) by CD38 itself (concentrative) or (ii) by nucleoside transporters (NT) (one equilibrative and three concentrative). Besides this autocrine mechanism, the same transporters also mediate intercellular (paracrine) trafficking. Thus, Cx43+ and CD38+ cells can provide cADPR to neighboring RyR+ parenchymal cells and enhance their [Ca2+]i levels and Ca2+-dependent functions accordingly. Examples of cADPR-responsive cells via paracrine processes include (i) smooth myocytes, (ii) 3T3 murine fibroblasts, (iii) hippocampal neurons, and (iv) human hemopoietic stem cells.