Human papillomaviruses (HPV) are the major factor in causing cervical cancer as well as being implicated in causing oral and anal cancers. The life cycle of HPV is tied to the epithelial differentiation system, as only native virus can be produced in stratified human skin. Initially, HPV research was only possible utilizing recombinant systems in monolayer culture. With new cell culture technology, systems using differentiated skin have allowed HPV to be studied in its native environment. Here, we describe current research studying native virions in differentiated skin including viral assembly, maturation, capsid protein interactions, and L2 cross-neutralizing epitopes. In doing so, we hope to show how differentiating skin systems have increased our knowledge of HPV biology and identify gaps in our knowledge about this important virus.