Human papillomaviruses are present in virtually all cervical cancers and cancer precursors. The transcriptional activity of the virus and the interactions of viral proteins with the epithelial cell determine the pathology of cervical neoplasia. Morphologic criteria are understandable relative to the 2 phenotypes of viral-host interaction (ie, a productive versus a proliferative phenotype). However, the subjective nature of morphologic interpretation has led to an increased utility of HPV and other molecular tests to increase both sensitivity and specificity of cervical cellular diagnosis. The development of HPV vaccines promises to dramatically impact the natural history of HPV infection.H uman papillomaviruses (HPVs) are necessary etiologic agents for cervical neoplasia. More than 2 decades of work has revealed the interplay of these common epitheliotropic viruses with cervical epithelial cells. The pathologic classification of cervical neoplasia, as well as the clinical management of these lesions, has been greatly influenced by these biologic insights. This essay will briefly review these concepts, with an emphasis on the mechanisms by which HPVs produce abnormal cervical morphology, as well as their role in the initiation and promotion of cervical cancer development. These concepts will then be extended to a discussion of the utility of HPV and related tests for diagnosis, as well as a preview of the upcoming event of HPV vaccine implementation.Ancient writings have described skin warts as a problem for humankind. In the beginning of the 20th century, Ciuffo 1 established the viral etiology of human warts (papillomas) by using cell-free extracts from wart tissue as an inoculum for human-to-human transmission experiments. Warts are present in essentially all vertebrate species in which they have been looked for. Shope and Hurst, 2 in 1933, described the first papillomavirus in cottontail rabbits (CRPV). Subsequent experimentation in this system, including the use of coal tar as a tumor promoter, stimulated early concepts of cancer initiation and promotion and confirmed CRPV as the first example of a DNA tumor virus. 2-4 The development of electron microscopy revealed the ultrastructural morphology of papillomaviruses. Clinical studies using electron microscopy revealed that certain kinds of warts were more productive of virions than others. For example, plantar warts often had abundant viral particles, whereas genital warts had relatively few. [5][6][7][8] Papillomaviruses are resistant to tissue culture, making the characterization of these viruses quite difficult. Biochemical and immunologic characterization carried out on viral proteins derived from direct extracts of warts suggested that there was a single type of HPV, an erroneous view that was held through the 1960s. 9 The subsequent revolution in modern biology permitted a more accurate characterization of the papillomavirus family. Clones of the HPV genomes were used to probe different pathologic processes and establish the relationship of those lesion...