Human papillomavirus (HPV) infection has variable clinical manifestations, from transient subclinical disease to serious cervical cancer precursors. An understanding of the natural history of this common sexually transmitted infection is necessary to allow diagnosis of clinically significant disease and judicious application of treatment modalities, especially in young adolescents. This article reviews new recommendations for initiation of screening, revisions in cytology terminology, and evidence-based guidelines for management of lower genital tract disease, including the application of HPV testing.