To extend our knowledge of host-cell targets of Helicobacter pylori, we characterized the interaction between H. pylori and human T84 epithelial cell polarized monolayers. Transcriptional analysis by use of human microarrays and a panel of isogenic H. pylori mutants revealed distinct responses to infection. Of the 670 genes whose expression changed, most (92%) required the cag pathogenicity island (PAI). Although altered expression of many genes was dependent on CagA (80% of the PAI-dependent genes), expression of >30% of these host genes occurred independent of the phosphorylation state of the CagA protein. Similarly, we found that injected CagA localized to the apical surface of cells and showed preferential accumulation at the apical junctions in a phosphorylation-independent manner. These data suggest the presence of distinct functional domains within the CagA protein that play essential roles in protein targeting and alteration of host-cell signaling pathways.