Stimulation of cells with physiological concentrations of calcium-mobilising agonists often results in the generation of repetitive cytoplasmic Ca2+ oscillations. Although oscillations arise from regenerative Ca2+ release, they are sustained by store-operated Ca2+ entry through CRAC channels. Ca2+ nanodomains near CRAC channels that open during the oscillatory cycle recruit local signalling pathways that lead to activation of NFAT transcription factors and increased expression of genes including c-fos and tumour necrosis factor-α. Stores communicate with CRAC channels through the ER Ca2+-sensing proteins STIM1 and STIM2. In this talk, we will describe our recent experiments that address the relative roles of STIM1 and STIM2 in maintaining Ca2+ oscillations and gene expression in mast cells. Our results reveal that different agonists utilise different STIM proteins to support Ca2+ signals and subsequent downstream responses. We will also compare gene knockdown strategies with pharmacological block of STIM proteins to address their relative contributions to physiological levels of Ca2+ signalling.