Human papillomavirus (HPV)-related cancers can be averted by type-specific vaccination (primary prevention) and/or through detection and ablation of precancerous cervical lesions (secondary prevention). This review presents current challenges to cervical cancer screening programs, focusing on recent molecular advances in HPV testing and potential improvements on risk stratification. Areas covered: High-risk (HR)-HPV DNA detection has been progressively incorporated into cervix cancer prevention programs based on its increased sensitivity. Advances in next-generation sequencing (NGS) are being rapidly applied to HPV typing. However, current HPV DNA tests lack specificity for identification of cervical precancer (CIN3). HPV typing methods were reviewed based on published literature, with a focus on these applications for screening and risk stratification in the emerging complex clinical scenario post-vaccine introduction. In addition, the potential for NGS technologies to increase specificity is discussed in regards to reflex testing of specimens for emerging biomarkers for cervix precancer/cancer. Expert commentary: Integrative multi-disciplinary molecular tests accurately triaging exfoliated cervical specimens will improve cervical cancer prevention programs while simplifying healthcare procedures in HPV-infected women. Hence, the concept of a ‘liquid-biopsy’ (i.e., ‘molecular’ Pap test) highly specific for early identification of cervical precancerous lesions is of critical importance in the years to come.