ORAI (ORAI1, ORAI2, and ORAI3) proteins form a family of highly Ca2+-selective channels at the plasma membrane. ORAIs are activated by stromal-interacting molecules (STIM1 and STIM2), which are Ca2+ sensing proteins located in the endoplasmic reticulum. STIM and ORAI proteins are ubiquitously expressed in all mammalian tissues and form store-operated Ca2+ entry (SOCE) channels. Mutations or altered expression of STIM and ORAI proteins are associated to a number of diseases, including cardiovascular and airway diseases and cancer. Here we will discuss our current understanding of ORAI channel signaling and regulation and their contribution to several pathologies.