© 2015 The Authors. Abstract Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3-/- mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3-/- mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension. Synopsis A systems biology approach integrating genome-wide genetic variation and transcriptome profiling data from participants of the Framingham Heart Study identifies key regulatory genes and gene networks underlying blood pressure control. Association analysis of blood pressure (BP) and gene expression levels identified individual genes and coexpression network modules that are correlated with BP. Incorporation of data from BP genome-wide association studies (GWAS) revealed four BP coexpression network modules (coEMs) that are enriched with eSNPs that demonstrate low P-values in BP GWAS. Further integration of the BP coEMs with molecular networks uncovered key driver genes that serve as network hubs to interconnect genes within the BP coEMs. One of the top key drivers, SH2B3, was analyzed in a Sh2b3-/- mouse model, which validated its effect on BP regulation and its central role in the BP subnetwork. A systems biology approach integrating genome-wide genetic variation and transcriptome profiling data from participants of the Framingham Heart Study identifies key regulatory genes and gene networks underlying blood pressure control.