Human cytomegalovirus induces a proinflammatory monocyte following infection, and we have evidence that NF-kappaB and phosphatidylinositol 3-kinase [PI(3)K] are key mediators in this early activation. To begin to address how these signaling pathways are responsible for the rapid activation of infected monocytes, we examined the role that these pathways played in the transcriptome of infected monocytes. Global transcriptional profiling using cDNA microarrays revealed that a significant number of genes, including inflammatory genes, were regulated in an NF-kappaB- and/or PI(3)K-dependent manner, identifying the NF-kappaB and PI(3)K pathways as key cellular control points in the conversion of monocytes to an activated proinflammatory state following HCMV infection.