Key proteins of the icosahedral-shaped adenovirus (Ad) capsid mediate infection, and interact with cellular proteins to coordinate stepwise events of cell entry that produce successful gene transfer. Infection is mediated predominantly by the penton and fiber capsid proteins. The fiber initiates cell binding while the penton binds integrin coreceptors, triggering integrin-mediated endocytosis. Penton integrin signaling precedes viral escape from the endosomal vesicle. After cell binding, the virus undergoes stepwise disassembly of the capsid, shedding proteins during cell entry. Intracellular trafficking of the remaining capsid shell is mediated by the interaction of naked particles with the cytoskeleton. The capsid translocates toward the nucleus, with the majority of capsid proteins accumulating at the nuclear periphery, while viral DNA and associated protein VII are extruded through the nuclear pore. This discussion will encompass the current knowledge on Ad cell entry and trafficking, with an emphasis on the contribution of Ad capsid proteins to these processes. A greater understanding of the highly effective Ad cell entry pathway may lend itself to the development of safer drug and gene delivery alternatives utilizing similar pathways.