Successful viral propagation relies on the careful regulation of cellular proteins. Controlling the cellular proteins that interact with viral genomes is an important regulatory strategy, since these interactions control a myriad of processes relevant to viral infection. Nuclear replicating DNA viruses face an especially difficult challenge, as their genomes are accessible to DNA-binding proteins that can promote or impair viral processes. Understanding the manipulation of host proteins associated with viral genomes provides insight into the role of cellular proteins in viral infection and provides targets for anti-viral therapeutics. Furthermore, these interactions can provide insight into the regulation of fundamental cellular processes, and have broader implications in understanding viral or cellular evolution. Here, we employed different strategies to understand how interactions with viral genomes are regulated. We studied adenovirus, a DNA virus that replicates in the nucleus, where its linear double-stranded DNA genome is accessible to nuclear DNA-binding proteins. First, we utilized evolutionary diverse adenovirus serotypes with distinct tissue tropisms to study interactions with known anti- viral proteins within the cellular DNA damage response (DDR). This project demonstrated that serotypes across the adenovirus family target DDR proteins, but do so with varying success. Some serotypes completely overcome inhibitory effects of the DDR, while other serotypes fail to do so. Further analysis demonstrated differences in the mechanisms used to target the DDR. Findings from this project showed that comparison of diverse adenovirus serotypes can provide mechanistic insight, and these findings may have broader implications in understanding tissue tropism and viral evolution. In the second project, we used proteomics to identify host proteins associated with viral genomes and uncovered a novel role for the histone-like viral protein VII in regulating these interactions. We found that protein VII promotes association of cellular proteins involved in transcription, splicing, and mRNA export. Furthermore, we found that protein VII suppresses the well characterized anti-viral interferon response. Together, our results demonstrate that defining interactions of cellular proteins with viral genomes is a useful strategy to identify cellular proteins that promote or impair viral processes and to understand viral mechanisms used to regulate their association with viral genomes.