Wherever cellular life occurs, viruses are also found. As a result, complex organism and cellular antiviral responses co-evolve with virally encoded countermeasures. Since viruses co-opt or interfere with specific cellular pathways during their replication, knowledge of viral genome sequences has helped fundamental understanding of host biology. During viral infection, shifts in the balance between host and viral biological processes result in acute or chronic viral disease pathology accompanied with either active viral replication, viral containment/persistence or viral clearance. Studying host-virus interactions at the level of single gene effects, however, fails to produce a global systems-level understanding. This should now be achievable in the context of complete host and pathogen genome sequences. New experimental methods and computational approaches are rapidly developing, allowing global views of dynamic viral and cellular molecular mechanisms. Systems level virology using DNA microarrays and specific viral data resources will reveal the detailed cellular context in which viruses replicate, highlighting common and distinct antiviral mechanisms, the effect of different host cell gene expression programs, and the response of cells to similar or diverse virus types. Ultimately, microbiology and immunology will tend towards a systems-level view of how host and pathogen interact.