Abstract  Store‐operated Ca2+ entry (SOCE) is a widespread mechanism in cells to raise cytosolic Ca2+ and to refill Ca2+ stores. T cells critically rely on SOCE mediated by stromal interaction molecules (STIM) and Orai molecules for their activation and regulation of gene transcription; cells such as muscle cells, neurons or melanocytes probably utilize SOCE for the transmission of inducible receptor‐mediated function as well as for generalized Ca2+ homeostasis mechanisms. Exposure to environmental or cell‐intrinisic reactive oxygen species (ROS) can affect several components involved in Ca2+ homeostasis and thus alter multiple pathways. While all cells have a capacity to produce intracellular ROS, exposure of immune and skin cells to extracellular oxidative stress is particularly high during inflammation and/or with UV exposure. This review briefly summarizes cell‐intrinsic sources of ROS and focuses on current findings and controversies regarding the regulation of STIM and Orai by oxidative modifications. We also introduce melanocytes as a new model system to study the function of STIM and Orai isoforms under physiological conditions that include exposure to UV light as an activating stimulus.