Cancer cells have the ability to become resistant to a variety of drugs, and apoptosis resistance of cancer cells is a major hindrance for effective therapeutic modalities. A panel of resistance markers is therefore urgently needed. Altered expression of ion channels is now recognized as one of the hallmarks of cancer [1]. Several ion channels have already been proposed as novel emerging biomarkers and targets for therapy in cancer [2]. Among them, calcium channels are of particular interest, calcium being a ubiquitous second messenger regulating a wide variety of physiological functions, including cell survival [3]. We have previously shown that Orai3 calcium channels are highly expressed in breast tumors and, to a lesser extent, in breast cancer cell lines. In addition, down-regulation of Orai3 expression decreases calcium entry and increases apoptosis specifically in breast cancer cells [4]. In this context, we wondered whether Orai3 overexpression would be able to confer resistance to breast cancer cells. The aims of this study were 1) to overexpress Orai3 in breast cancer cells, 2) to study the impact on calcium entry and cell survival, and 3) to decipher the molecular mechanisms involved in Orai3-conferred resistance. Stable clones derived from the T47D breast cancer cell line were selected. Orai3 overexpression increases calcium entry, and decreases cell mortality after treatment with apoptosis inducers (thapsigargin, staurosporin) and chemotherapeutic drugs used for breast cancer treatment (cisplatin, 5-fluorouracil, paclitaxel). This resistance is calcium-dependent since cells overexpressing Orai3 lose their resistance to death when extracellular calcium is removed. In order to decipher the mechanism by which Orai3 can confer resistance to cell death, we conducted a high throughput screening using DNA micro-chips. This whole genome transcriptomic analysis revealed a down-regulation of apoptotic genes expression regulated by p53, a ‘tumor suppressor gene’-encoded transcription factor, whose expression also decreases in cells overexpressing Orai3. Furthermore, the expression of Bax, a pro-apoptotic p53 target, decreases in these cells, and the expression of anti-apoptotic Bcl-2 increases. In conclusion, Orai3 overexpression in breast cancer cells confers resistance to cytotoxic and chemotherapeutic drugs via a down-regulation of p53 and its pro-apoptotic targets expression and up-regulation of Bcl-2 expression. These results highlight a new marker of resistance, whose presence in tumors could indicate higher resistance to drugs, pointing toward requirements for more adapted treatments.