Ca2+ release-activated Ca2+ (CRAC) channels were originally identified as store-operated highly selective Ca2+ channels in primary rat mast cells and Jurkat T cells (Hoth & Penner, 1992; Zweifach & Lewis, 1993), but have since been identified in many cell types. While STIM1 and Orai1 constitute the main subunits of CRAC channels in lymphocytes, other cell types contain different combinations/ratios of Orai1, Orai2 or Orai3 and STIM1 or STIM2. We are interested in physiological and pathophysiological regulation of CRAC channels by environmental factors such as oxidation, as well as by posttranslational alterations of their glycosylation status. We have shown that Orai1 channels but not Orai3 channels are inhibited by extracellular applied ROS and that C195 is mainly responsible for mediating this effect (Bogeski et al, 2010). But how does oxidation of C195 affect function? What if the channels are heteromers between Orai1 and Orai3? Current studies investigate these questions by analyzing diffusional properties (FRAP), clustering (TIRF) and heteromerization of Orai channels. In addition to functional regulation by extracellular ROS, we are interested to find out if and how T-cell function controlled by CRAC is regulated by altered glycosylation patterns. Changes in the extracellular composition of T-cell glycans are likely involved in physiological and pathophysiological dysregulation of T-cell function during ageing and in certain diseases, e.g. diabetes. Both STIM proteins are predominantly ER resident proteins showing basal glycosylation patterns. Mutations of the N-glycosylation sites of STIM1 regulate Ca2+ influx by altered oligomerization of STIM1 and by destabilization of the Ca2+ channel Orai1 (Kilch et al, 2013). In contrast, Orai1 is a complex glycosylated protein. We show that Orai1 glycosylation is cell-type specific and that given the correct repertoire of specific glycosyltransferases the glyco-fingerprint of Orai1 can affect localization and function in calcium signaling.