Viruses, as obligate intracellular pathogens, rely on their host cell for successful replication. Viruses have evolved different strategies to hijack and redirect cellular processes to benefit infection and overcome host immune responses. Understanding the mechanisms by which viruses exploit their host cells will reveal new targets for antiviral therapies. In addition, these studies can provide insights into the regulation of fundamental cellular processes. While much progress has been made in this area, many unexpected nuances of virus-host interaction are still being discovered. Here, we employed several strategies to uncover new aspects of viral manipulation of the host environment by adenovirus, a nuclear-replicating DNA virus that commonly infects humans. The first project focused on how viral histone-like proteins impact cellular chromatin. Adenovirus encodes the small, basic protein VII that coats and condenses viral genomes. The effect of this viral DNA-binding protein on host chromatin structure and function had remained unexplored. Here we demonstrated that protein VII interacts with host nucleosomes and is sufficient to alter nuclear morphology. We also identified post-translational modifications of protein VII that regulate chromatin association. Through a proteomics analysis of chromatin composition, we revealed that protein VII causes nuclear retention of HMGB1, a host alarmin, and reduces downstream inflammation. The second project examined roles of viral-mediated ubiquitination during infection. Ubiquitination of host proteins, mediated by adenovirus proteins E1B55K and E4orf6, is important for viral RNA processing. However, previously identified substrates of viral-mediated ubiquitination do not explain this phenotype. Here we used a proteomics approach to define new substrates of the E1B55K/E4orf6 complex. We uncovered viral-mediated ubiquitination of RNA-binding proteins (RBPs) which, unlike ubiquitination of other substrates, does not result in proteasomal degradation. We furthermore demonstrated that ubiquitination of RBPs RALY and hnRNP-C decreases their binding to viral RNA and relieves a restriction these host proteins exert on adenovirus RNA processing. Our study of adenovirus proteins revealed new strategies employed by viruses to alter host functions: manipulating host chromatin through viral histone-like proteins to dampen immune responses and regulating RNA processing by non-degradative ubiquitination of cellular RBPs.