Adenovirus is a common infectious pathogen in both children and adults. It is a significant cause of morbidity in immunocompetent people living in crowded living conditions and of mortality in immunocompromised hosts. It has more recently become a popular vehicle for gene therapy applications. The host response to wild-type infection and gene therapy vector exposure involves both virus entry receptor and the innate immune systems. Cell-mediated recognition of viruses via capsid components has received significant attention, principally thought to be regulated by the coxsackievirus-adenovirus receptor (CAR), CD46, integrins and heparin sulfate-containing proteoglycans. Antiviral innate immune responses are initiated by the infected cell, which activates the interferon response to block viral replication, while simultaneously releasing chemokines to attract neutrophils and NK cells. This review discusses the innate immune response primarily during wild-type adenovirus infection because this serves as the basis for understanding the response during both natural infection and exposure to adenovirus vectors.