Papillomaviruses induce proliferative skin lesions that are normally benign, but which occasionally progress to malignant carcinomas such as cervical cancer. The viral E1 and E2 genes encode multiple gene products that regulate viral transcription and replication and our objective is to understand the mechanisms by which they control the viral life cycle. The full-length E1 gene product is the predominant protein required for viral DNA replication but it also functions as a transcriptional repressor. We have shown that a large C-terminal domain of the E1 protein is necessary for origin-specific binding and interaction with the E2 protein and we find that this domain is sufficient to support transient viral DNA replication and transcriptional repression in vivo. The E2 transactivator protein is required for viral transcriptional regulation and DNA replication and may be important for long term episomal maintenance of viral genomes. We have shown the E2 transactivator protein and BPV-1 viral genomes are associated with mitotic chromosomes and we have proposed a model whereby E2-bound viral genomes are transiently associated with condensed cellular chromosomes during mitosis. This would ensure that viral genomes are segregated to daughter cells in approximately equal numbers.