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The pannexin (Panx) family, which is coexpressed with connexins (Cxs) in vertebrates, was found to be a new GJ-forming protein family related to invertebrate innexins. During the past ten years, different studies showed that Panxs mainly form hemichannels in the plasmamembrane and mediate paracrine signalling by providing a flux pathway for ions such as Ca2+ , for ATP and perhaps other compunds, in response to physiological and pathological stimuli. Although different studies questioned the physiological role of Panxs as a hemichannel, it is clear that Panx play a role in long-range Ca2+-wave propagation, vasodilatation, initiation of inflammatory responses, ischemic death of neurons, epilepsy and in tumor suppression. Moreover, it is intruiging that Panxs may also function as intracellular Ca2+-leak channel and may be involved in ER-related functions.. Although the physiological significance and meaning of such Panx-regulated intracellular Ca2+-leak remain largely unexplored, this functional property puts Panxs at the centre of many physiological and pathophysiological processes, given the fundamental role of intracellular Ca2+ homeostasis and dynamics in a plethora of physiological processes. In this review we therefore want to focus on Panx channels as release channels with a particular emphasis on its role as an intracellular Ca2+-leak channel.