There are 3 Orai and 6 TRPC proteins in humans. Each is a membrane protein, spanning the membrane 4 times (Orais) and, putatively, 6 times (TRPCs). TRPCs are about 4 bigger than the Orais and they are clearly distinct protein families. The Orais assemble as homo or hetero hexamers to form ion channels where as the TRPCs are thought to form separate ion channels as homo or hetero tetramers. In both cases the channels enable influx of the calcium ion, a master intracellular regulator that impacts on excitable and non-excitable cell functions. In several cases there is also sodium ion influx which may have direct functional effects or indirect effects through calcium signaling. All Orais and TRPCs have been reported to be expressed in the cardiovascular system. It has been more than a decade since TRPCs were first investigated where as Orais have emerged only in the past few years. The importance, properties and regulation of the channels is an important subject of on-going investigation. Many aspects remain unclear, including the intriguing question of the inter-relationship between the Orai and TRPC channels in the context of intracellular calcium store depletion. My research addresses fundamental understanding of how and why cells control calcium ion entry in vascular biology, particularly in adaptive processes, human disease and therapeutics. Orais and TRPCs are therefore a major aspect of this research. We have been interested in the physiological and pathophysiological activators of the channels in different contexts of cardiovascular biology, including regulation by lipid factors, growth factors (VEGF, PDGF), and ER stress (E AL-Shawaf et al 2010 ATVB; J Li et al 2011 Circ Res; L McKeown et al 2012 Circ Res; P Sukumar et al 2012 Circ Res). Recent findings will be discussed. The research is supported by the Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, BBSRC, and AstraZeneca.