Low-cost DNA sequencing has greatly democratized genomics, especially for the typically very small genomes of viruses [1]–[3]. The recent acceleration in human virus discovery by metagenomics indicates that many viruses escaped prior detection due to limitations of preexisting technologies. It is now conceivable that all viral species commonly infecting human (i.e., the human virome) will soon be determined. As the value of the human genome and microbiome has become widely recognized, providing crucial reference genomes and opening unanticipated avenues of research, the genetic characterization of the human virome also holds great promises [4]. The human microbiome project, focusing largely on single bacterial cells and metagenomic sequencing of total DNA from feces and other human sites, is unlikely to detect RNA viruses. The generally minuscule size of viral genomes relative to those of their bacterial or eukaryotic hosts also weighs against their easy detection in metagenomic approaches. Viral discovery can be greatly facilitated by simple filtration to enrich the smaller viral particles and by removal of contaminating bacterial and human nucleic acids using nuclease digestion that leave viral nucleic acids protected within their virion shells (Figure 1) [5]. Density gradient ultra-centrifugation has also been used to enrich viral particles. Figure 1 Schematic steps for determination of human virome and its impact on health, including biological samples and data acquisition, genetic analysis, and epidemiology of viral infections. Knowledge of the human virome will allow the design of sensitive and specific tests to all human viruses using “virochip” microarrays [6] or multiplexed PCR assays (Figure 1). Provided samples from large enough human cohorts are analyzed, it will be possible to determine viral prevalence, likely transmission routes, and most crucially disease association. The development of vaccines and antivirals can then be targeted to the viruses with the largest public health impacts in different geographic regions. Deciphering the complete human virome will therefore improve our understanding, prevention, and treatment of currently unexplained diseases involving viral pathogens, as well as provide insights into the evolution of viral families and cross-species viral transmissions. Despite the rapid progress being made toward deciphering the human virome, several roadblocks remain to its full characterization and utilization. Below is an abbreviated list of these problems and possible solutions.