Modern laboratory techniques for the detection of novel human viruses are greatly needed as physicians and epidemiologists increasingly deal with infectious diseases caused by new or previously unrecognized pathogens. There are many clinical syndromes in which viruses are suspected to play a role, but for which traditional microbiology techniques routinely fail in uncovering the etiologic agent. In addition, new viruses continue to challenge the human population owing to the encroachment of human settlements into animal and livestock habitats, globalization, climate change, growing numbers of immunocompromised people and bioterrorism. Metagenomics-based tools, such as microarrays and high-throughput sequencing are ideal for responding to these challenges. Pan-viral microarrays, containing representative sequences from all known viruses, have been used to detect novel and distantly-related variants of known viruses. Sequencing-based methods have also been successfully employed to detect novel viruses and have the potential to detect the full spectrum of viruses, including those present in low numbers.