We have used Compugen human 19K oligonucleotide arrays to study the host response to dengue infection, initially in a human hepatocytic cell line (HepG2). We identified the upregulation of three major clusters of genes; NF-kB-mediated cytokine/chemokine responses, type I IFN response, and the ubiquitin-proteasome system. Increased expression of selected genes, identified by Compugen array, was confirmed using a taqman low density array (TLDA) and results extended to include an additional, readily infectable, cell line (A549) and PBMC derived from adult dengue fever patients from a Singapore dengue prospective cohort study. Next we sought to confirm the functional effects of these upregulated genes. We confirmed the high levels of two novel chemokines, IP-10 and I-TAC, in dengue infection, in both cell lines and in dengue patients. We also determined that overexpression of viperin, an upregulated gene in the IFN pathway, and proteasome inhibition, with MG-132 or ALLN, reduced virus replication. In summary, we have used microarray analysis to identify new host genes associated with dengue infection, and to show that components of the host response can control dengue viral replication and therefore represent potential targets for drug therapy.