Of the established Ca2+ mobilizing messengers, Nicotinic acid adenine dinucleotide phosphate (NAADP) is arguably the most intriguing. It is the most potent, often working at low nanomolar concentrations. Unlike other Ca2+ mobilizing messengers such as inositol trisphosphate (IP3) and cyclic ADP-ribose (cADPR) which release Ca2+ from the endoplasmic reticulum, NAADP mobilizes calcium from acidic stores, including lysosomes, representing a new function for this organelle. Recent work has identified a new class of calcium release channel, the two pore channels (TPCs), as the likely targets for NAADP (1,2). These channels are endolysosomal in localization where they mediate local Ca2+ release. Three distinct roles of these NAADP-regulated channels have been identified. The first is to regulate local Ca2+ release that may play a role in endolysosomal functions including fusion and trafficking (3). The second is to trigger global Ca2+ release by recruiting Ca2+ -induced Ca2+ release (CICR) channels at lysosomal-endoplasmic reticulum junctions (1,3). The third is to regulate plasma membrane excitability by the targeting of Ca2+ release from sub-plasma membrane stores to activate plasma membrane calcium-activated channels (1). In this talk, I will discuss the role of lysosome-based NAADP-mediated Ca2+ release as a widespread trigger for intracellular calcium signalling and how studies of TPCs have enhanced our understanding of this process.