The most compelling question in evaluating the possible replacement of the conventional Papanicolaou smear from a high-risk HPV testing method is the balance between specificity and sensitivity for detection of cervical intraepithelial neoplasia grade ≥CIN 2 (CIN 2+). Multiple studies have shown that HPV testing has higher sensitivity than cytology for the detection of high-grade CIN. Positivity increases the test cut-off for HPV and may reduce false positive results without significantly compromising the sensitivity, potentially alleviating the concern of low specificity. Overall, available evidence convincingly shows that HPV testing is superior to traditional screening for the detection of high-grade cervical lesions, and efforts are focused on improving its sensitivity, either by increasing its cut-off for positivity or by selecting those subgroups where HPV testing is expected to have higher positive predictive value for cervical disease, or by seeking to optimize triage tests after a positive HPV result.