Eukaryotic cells orchestrate constant synthesis and degradation of intracellular components, including soluble proteins and organelles. The two major intracellular degradation pathways are the ubiquitin/proteasome system and autophagy. Whereas ubiquitin/proteasome system is involved in rapid degradation of proteins, autophagy selectively removes protein aggregates and damaged organelles. Failure of these highly adjusted proteolytic systems to maintain basal turnover leads to altered cellular homeostasis. During evolution, certain viruses have developed mechanisms to exploit their functions to facilitate their own replication, prevent viral clearance and promote the outcome of infection. In this article, we summarize the current opinion on adenoviruses (Ad) and molecular host cell targets, extending on recent evidences for protein degradation pathways in infected cells. We describe recently identified connections between Ad-mediated proteolysis and viral replication with main emphasis on the function of certain Ad proteins.