More than 80 different adenovirus (AdV) types infect humans through the respiratory, ocular, or gastrointestinal tracts. They cause acute clinical manifestations or persist under humoral and cell-based immunity. Immuno-suppressed individuals are at risk of death from an AdV infection. Concepts about cell entry of AdV build on strong foundations from molecular and cellular biology—and increasingly physical virology. Here, we discuss how virions enter and deliver their genome into the nucleus of epithelial cells. This process breaks open the virion at distinct sites because the particle has nonisometric mechanical strength and reacts to specific host factors along the entry pathway. We describe how macrophages and dendritic cells resist AdV infection yet enhance productive entry into polarized epithelial cells. A deep understanding of the viral mechanisms and cell biological and biophysical principles will continue to unravel how epithelial and antigen-presenting cells respond to AdVs and control inflammation and persistence in pathology and therapy. Expected final online publication date for the Annual Review of Virology Volume 6 is September 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.