Risk management efforts in the cytology laboratory must address the gap between what can be achieved with medical history's most effective cancer screening test, the Papanicolaou (Pap) test, and even higher entrenched public expectations. Data from the Atypical Squamous Cells of Undetermined Significance (ASCUS)/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) now provide level I clinical evidence from a large, randomized, controlled, multicenter clinical trial that reflex human papillomavirus (HPV) DNA testing of ASCUS cases is generally the preferred method for initial assessment of the most prevalent category of abnormal Pap interpretation. The proposed combination of HPV DNA testing with cytologic Pap testing, the DNA Pap test, further shows the potential to nearly eliminate false-negative screening results, based on sensitivity and negative predictive values reported in available studies. Human papillomavirus DNA testing also appears to represent a significant enhancement for detection of endocervical adenocarcinomas, which are difficult to detect and prevent. Human papillomavirus DNA testing, when used in conjunction with cervical cytology, can significantly reduce risk to both the patient and the laboratory.