Ultraviolet (UV) radiation of the skin triggers keratinocytes to secrete endothelin-1 (ET-1) which binds to endothelin receptors on neighboring melanocytes. Melanocytes respond with a prolonged increase in intracellular Ca²⁺ concentration which is necessary for proper cellular function. A major fraction of the Ca²⁺ signal is caused by entry through Ca²⁺ permeable channels of unknown identity in the plasma membrane. ORAI Ca²⁺ channels are molecular determinants of Ca²⁺ release-activated Ca²⁺ (CRAC) channels and are expressed in many tissues. Here, we show that ORAI1-3 and their activating partners stromal interaction molecules 1 and 2 (STIM1 and STIM2) are expressed in human melanocytes. While ORAI1 is the predominant ORAI isoform, STIM2 mRNA expression exceeds STIM1. Inhibition of ORAI1 by 2-aminoethoxydiphenyl borate (2-APB) or down-regulation of ORAI1 by siRNA reduced Ca²⁺ entry and CRAC current amplitudes in activated melanocytes. In addition, melanocyte viability, melanin synthesis and tyrosinase activity were decreased upon stimulation with ET-1 in melanocytes with suppressed ORAI1 function. These results indicate that ORAI1 Ca²⁺ channels control melanocyte mito- and melanogenesis and also suggest that they are involved in UV-induced skin tanning and in melanoma growth and metastasis.