Orai proteins form highly calcium (Ca2+)-selective channels located in the plasma membrane of both nonexcitable and excitable cells, where they make important contributions to many cellular processes. The well-characterized Ca2+ release-activated Ca2+ current is mediated by Orai1 multimers and is activated, upon depletion of inositol 1,4,5-trisphosphate-sensitive stores, by direct interaction of Orai1 with the endoplasmic reticulum Ca2+ sensor, stromal interaction molecule 1 (STIM1). This pathway is known as capacitative Ca2+ entry or store-operated Ca2+ entry. While most investigations have focused on STIM1 and Orai1 in their store-dependent mode, emerging evidence suggests that Orai1 and Orai3 heteromultimeric channels can form store-independent Ca2+-selective channels. The role of store-dependent and store-independent channels in excitation-transcription coupling and the pathological remodeling of the cardiovascular system are beginning to come forth. Recent evidence suggests that STIM/Orai-generated Ca2+ signaling couples to gene transcription and subsequent phenotypic changes associated with the processes of cardiac and vascular remodeling. This short review will explore the contributions of native Orai channels to heart and vessel physiology and their role in cardiovascular diseases.