Viral metagenomics has revolutionized our understanding for identification of unknown or poorly characterized viruses. For that reason, metagenomic studies gave been largely applied for virus discovery in a wide variety of clinical samples, including blood specimens. The emerging blood-transmitted virus infections represent important problem for public health, and the emergence of HIV in the 1980s is an example for the vulnerability of Blood Donation systems to such infections. When viral metagenomics is applied to blood samples, it can give a complete overview of the viral nucleic acid abundance, also named “blood virome”. Detailed characterization of the blood virome of healthy donors could identify unknown (emerging) viral genomes that might be assumed as hypothetic transfusion threats. However, it is impossible only by application of viral metagenomics to assign that one viral agent could impact blood transfusion. That said, this is a complex issue and will depend on the ability of the infectious agent to cause clinically important infection in blood recipients, the viral stability in blood derivatives and the presence of infectious viruses in blood, making possible its transmission by transfusion. This brief review summarizes information regarding the blood donor virome and some important challenges for use of viral metagenomics in hemotherapy for identification of transfusion-transmitted viruses.