Pathogens exploit cellular resources for their own benefit and their propagation. Co-evolution of viruses and their hosts led to the establishment of very specific interactions between both partners. The balance between both, the viral attack and the cellular defense mechanisms, dictates the outcome of an infection, either leading to a cure, to disease or life-long co-existence. Efforts from many laboratories have focused on virus-host interactions, mostly by testing isolated protein-protein interactions or by employing transcriptome analysis. Although this undoubtedly has been highly valuable to our knowledge on virus-host interactions, it is also clear that most virus-host interactions do not occur on transcriptome level and neither involve single protein-protein interactions. Here I propose to systematically test the impact of virus infection on the host proteome (iViP) by using the newest generation of mass spectrometry-based discovery tools combined with infection biology. iViP divides in three interconnected parts that individually and collectively warrant success: Part I evaluates changes in the abundance of the proteins after virus infection and correlates this to mRNA levels, determined by RNA sequencing. Part II identifies proteome-wide post-translational modifications that would be indicative for an involvement in infection biology. Part III dissects the role of virus stimulated/altered proteins in the antiviral protein-protein interaction network. Lastly, identified proteins will be validated in a two –step procedure involving a large-scale validation strategy and further focusing on few selected interactors. A comprehensive coherent data set describing and functionally explaining the cellular changes after encounter of a variety of viral pathogens on a proteome level would complement or even succeed currently available data sets and become invaluable to basic and translational research of the future.