There is justifiable excitement about the recent introduction of prophylactic vaccines against human papillomavirus (HPV) types 16 (HPV-16) and HPV-18. Preventing these infections theoretically could avert approximately 70% of cervical cancer cases worldwide. In the U.S., numerous influential advocates are calling for universal vaccination of adolescent females. Given the promise of the vaccines, perhaps it is inevitable that vaccine introduction is proceeding before full consideration of how universal vaccination would affect existing, successful cervical cancer prevention programs. Determining the impact and cost effectiveness of the vaccines unavoidably will require time. Nevertheless, it is worth describing in broad terms for the readers of Cancer Cytopathology how successful, broad HPV vaccination of adolescent girls may affect cytology and HPV testing. Cancer (Cancer Cytopathology) 2007. © 2007 American Cancer Society.