Dengue virus infection is a global health concern, affecting as many as 100 million people annually worldwide. A critical first step to proper treatment and control of any virus infection is a correct diagnosis. Traditional diagnostic tests for viruses depend on amplification of conserved portions of the viral genome, detection of the binding of antibodies to viral proteins, or replication of the virus in cell cultures. These methods have a major shortcoming: they are unable to detect divergent or novel viruses for which a priori sequence, serological, or cellular tropism information is not known. In our study, we use two approaches, microarrays and deep sequencing, to virus identification that are less susceptible to such shortcomings. We used these unbiased tools to search for viruses in blood collected from Nicaraguan children with clinical symptoms indicating dengue virus infection, but for whom current dengue virus detection assays yielded negative results. We were able to identify both known and divergent viruses in about one third of previously negative samples, demonstrating the utility of these approaches to detect viruses in cases of unknown dengue-like illness. denatured at 95uC for 2 min, cooled briefly on ice, then fluorescently labeled in reactions containing 100 mM sodium bicarbonate pH 9, 10% DMSO, and 667 mM Cy3 mono NHS ester (GE Healthcare) for 1 hour at 25uC. Labeled DNA was purified using DNA-CC-5 columns and added to hybridization reactions containing 36SSC, 25 mM HEPES pH 7.4, and 0.25% SDS. Hybridization mixtures were heated at 95uC for 2 minutes, applied to microarrays, and hybridized overnight at 65uC. Following hybridization, arrays were washed twice in 0.576 SSC and 0.028% SDS and twice in 0.0576SSC, then scanned on an Axon GenePix 4000B microarray scanner. Three analysis tools were used to analyze Virochip data: E-predict [33] , Z-score analysis [34] , and cluster analysis [35] . An array was deemed positive for a particular virus if the virus was identified by at least two of these methods. Virochip results were deposited in the NCBI GEO database (GEO accession series: GSE28142).