This review by Anna Kirk and Sheila V. Graham from the Centre for Virus Research at the University of Glasgow provides an in-depth analysis of the late gene expression in human papillomavirus (HPV) infections and its links to keratinocyte differentiation. HPV gene expression is tightly regulated and confined to the upper layers of the epithelium, where the capsid proteins are synthesized. This spatial restriction aids immune evasion due to the immunogenic nature of these proteins and the immune-privileged status of the upper epithelium. The review covers the molecular and cellular mechanisms controlling late gene expression, including transcriptional and posttranscriptional regulation, splicing, polyadenylation, and mRNA stability. It also discusses the role of host cell signaling, particularly the innate immune response, in modulating late gene expression. The authors highlight the importance of understanding these mechanisms for developing novel antiviral strategies, such as targeting specific viral proteins or disrupting the viral life cycle at key stages. The review concludes by emphasizing the need for further research to fully understand the differentiation-specific late events in the HPV life cycle, which could lead to the development of more effective therapies against HPV infection.This review by Anna Kirk and Sheila V. Graham from the Centre for Virus Research at the University of Glasgow provides an in-depth analysis of the late gene expression in human papillomavirus (HPV) infections and its links to keratinocyte differentiation. HPV gene expression is tightly regulated and confined to the upper layers of the epithelium, where the capsid proteins are synthesized. This spatial restriction aids immune evasion due to the immunogenic nature of these proteins and the immune-privileged status of the upper epithelium. The review covers the molecular and cellular mechanisms controlling late gene expression, including transcriptional and posttranscriptional regulation, splicing, polyadenylation, and mRNA stability. It also discusses the role of host cell signaling, particularly the innate immune response, in modulating late gene expression. The authors highlight the importance of understanding these mechanisms for developing novel antiviral strategies, such as targeting specific viral proteins or disrupting the viral life cycle at key stages. The review concludes by emphasizing the need for further research to fully understand the differentiation-specific late events in the HPV life cycle, which could lead to the development of more effective therapies against HPV infection.