The nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) family of transcription factors is a key component of the host innate immune response to infectious adenoviruses and adenovirus vectors. In this review, we will discuss a regulatory adenoviral protein encoded by early region 3 (E3) called E3-RIDα, which targets NFκB through subversion of novel host cell pathways. E3-RIDα down-regulates an EGF receptor signaling pathway, which overrides NFκB negative feedback control in the nucleus, and is induced by cell stress associated with viral infection and exposure to the pro-inflammatory cytokine TNF-α. E3-RIDα also modulates NFκB signaling downstream of the lipopolysaccharide receptor, Toll-like receptor 4, through formation of membrane contact sites controlling cholesterol levels in endosomes. These innate immune evasion tactics have yielded unique perspectives regarding the potential physiological functions of host cell pathways with important roles in infectious disease.