Regulation of organellar fusion and fission by Ca ( 2+) has emerged as a central paradigm in intracellular membrane traffic. Originally formulated for Ca ( 2+) -driven SNARE-mediated exocytosis in the presynaptic terminals, it was later expanded to explain membrane traffic in other exocytic events within the endo-lysosomal system. The list of processes and conditions that depend on the intracellular membrane traffic includes aging, antigen and lipid processing, growth factor signaling and enzyme secretion. Characterization of the ion channels that regulate intracellular membrane fusion and fission promises novel pharmacological approaches in these processes when their function becomes aberrant. The recent identification of Ca ( 2+) permeability through the intracellular ion channels comprising the mucolipin (TRPMLs) and the two-pore channels (TPCs) families pinpoints the candidates for the Ca ( 2+) channel that drive intracellular membrane traffic. The present review summarizes the recent developments and the current questions relevant to this topic.