Several randomized trials have demonstrated that HPV-based cervical cancer screening is more effective than cytology-based screening. A pooled analysis of long-term follow-up data from these trials has shown reduced cervical cancer mortality in women screened with HPV compared to cytology. As a consequence, many health systems are currently transitioning to HPV-based screening programs. However, there are several controversies that influence whether and how HPV-based cervical cancer screening is implemented in different settings. Here, we discuss the most important controversies surrounding cervical cancer screening using primary HPV testing in light of published data from clinical trials and large observational studies. Overall, there is strong and uniform evidence for the efficacy of HPV-based screening, and little evidence for the usefulness of adding cytology to primary screening. However, there is currently limited data on optimal triage strategies for HPV-positive women, a critical component of an HPV-based screening program. There will likely be multiple choices for integrated screening programs and implementation may differ depending on risk perception, healthcare funds, assay costs, and available infrastructure, among other factors, in different settings. A particular challenge is the integration of screening and vaccination programs, since increasingly vaccinated populations will have a continuous decrease of cervical cancer risk.