HPVs are small DNA tumor viruses with an icosahedral virion structure. All members of the genus cause diverse benign lesions, and some members promote the development of carcinoma. The viruses do not replicate in culture without extraordinary measures, and virtually all studies to date have used molecular methods to elucidate their biology and natural history. Tests of choice for detecting HPV from clinical specimens are based on nucleic acid probe technology. Until recently, most epidemiologic and molecular studies employed Southern blot (SB), dot blot (DB), and in situ hybridization (ISH). With the exception of ISH, which continues to have many uses and a strong following in the pathology community, SB and DB have been essentially replaced by polymerase chain reaction (PCR) and the Hybrid Capture System (HCS). These newer in vitro probe tests have proven to be accurate and robust workhorses for epidemiologic and clinical use. Automation promises to revolutionize HPV testing in the near future and will allow cost-effective mass screening worldwide.