Twenty years have passed since the first studies using human papillomavirus (HPV) testing began in clinical settings. At that time controversy regarding the role of HPV in cervical carcinogenesis still divided the scientific world. Epidemiological and natural history studies on HPV and cervical cancer in the ensuing two decades secured the necessary role of high-risk (carcinogenic) HPV in the genesis of cervical cancer, providing the rationale for testing for its cause. Subsequently, cross sectional studies and large randomized trials have provided clinical validation for high-risk HPV testing in triage of atypical squamous cells of undetermined significance (ASC-US), in postcolposcopy management of women referred for ASC-US, atypical squamous cells "cannot rule out high grade" (ASC-H), atypical glandular cells "not otherwise specified" (AGC NOS) and low grade squamous intraepithelial lesion (LSIL) and not found to have cervical intraepithelial neoplasia (CIN) 2+ or adenocarcinoma in situ (AIS) at initial colposcopy, in post-treatment of CIN 2+ surveillance, and in cotesting with the Papanicolaou (Pap) test of women age 30 and over. This is the story of the road traveled that brought the clinical use of HPV testing from its genesis only a few years after Dr. zur Hausen's discovery to its present eminent role in both primary cervical cancer screening and abnormal Pap management.