Alterations in the vasculature during hypertension include smooth muscle hyperplasia and hypertrophy, yet the changes in gene expression underlying these events are unknown. Previous data have shown that arteries from hypertensive animals exhibit elevated cytoplasmic Ca²⁺ and increased activation of both the Ca²⁺/cAMP response element binding protein (CREB) and the MAP kinase, ERK. Multiple Ca²⁺ entry pathways induce CREB activation in vascular smooth muscle including entry through voltage-dependent Ca²⁺ channels (VDCC) and store-operated Ca²⁺ entry (SOCE). In the current study, microarray analysis was used to test the hypotheses that 1) Ca²⁺ entry induced by distinct stimuli differentially regulates gene expression in cultured human cerebrovascular smooth muscle cells and 2) cerebral arteries obtained from humanely killed Dahl S hypertensive rats exhibit increased expression of CREB- and ERK-regulated genes. Microarray results were validated and expanded using quantitative RT-PCR and parallel measurements of protein expression using western blot analysis and immunocytochemistry. Results indicate that the activation of different Ca²⁺ influx pathways stimulates transcription of both distinct and overlapping sets of genes and that the induction is prevented by the addition of corresponding Ca²⁺ channel blockers. In addition, arteries from hypertensive animals exhibit increased transcription of the Ca²⁺– and proliferation-related genes c-fos, egr-2 and osteopontin, as well as eEF2K, a negative regulator of translation. We propose that during hypertension, overactivity of Ca²⁺ entry pathways and ERK in vascular smooth muscle leads to expression of specific sets of genes that regulate cell proliferation and hypertrophy. Together, these results suggest precise coupling of Ca²⁺ excitation pathways to transcriptional programs that may reveal future targets for therapies to prevent hypertension-related arterial pathologies.