Gene expression profiles were generated using cDNA microarray technology for clones of HEK-293 cells selected to have either high or low levels of store-operated Ca²⁺ entry (SOCE). For five high clones, three low clones and control HEK-293 cells, duplicate Affymetrix U133A human gene arrays were run after extracting total RNA from cells growing in the presence of serum. Of the ~22,000 genes represented on the microarray, 58 genes had readings at least 2-fold higher, while 32 genes had readings at least 2-fold lower, in all 5 high SOCE clones compared to control HEK-293 cells. In the low SOCE clones, 92 genes had readings at least 2-fold higher, while 58 genes had readings at least 2-fold lower, than in HEK-293 cells. Microarray results were confirmed for 18 selected genes by real time RT-PCR analysis; for 6 of those genes, predicted changes in the low SOCE clone were confirmed by an alternative method, monitoring mRNA levels in HEK-293 with SOCE decreased by expression of siRNA to TRPC1. Genes regulated by SOCE are involved in signal transduction, transcription, apoptosis, metabolism and membrane transport. These data provide insight into the physiological role of SOCE. In addition, a potential regulator of SOCE, insulin receptor substrate 2 (IRS-2), has been identified. A reduction of IRS-2 levels by siRNA methods in two high clones dramatically reduced SOCE, while overexpression of IRS-2 in a low SOCE clone elevated SOCE.