In 2016, the Netherlands will switch, as first European country, from cytology-based to HPV-based cervical cancer screening, with cytology triage for those with a positive HPV test. The new Dutch program includes sending self-sampling devices to women who do not respond to an invitation to have a cervical sample taken by their general practitioner. The cost-effectiveness of this additional strategy will depend on its capacity to recruit nonscreened women and in particular those at increased risk of cervical (pre)cancer, the possible switch of previous responders to self-sampling, the accuracy and cost of the HPV assay-self-sampler combination, and the compliance of women being self-sample HPV-positive with further follow-up. Validated PCR-based assays, detecting high-risk HPV DNA, are as accurate on self-samples as on clinician-collected samples. On the contrary, HPV assays, based on signal amplification, are less sensitive and specific on self-samples. The introduction of self-sampling strategies should be carefully prepared and evaluated in pilot studies integrated in well-organized settings before general rollout. Opt-in procedures involving a request for a self-sampler may reduce response rates. Therefore, an affordable device that can be included with the invitation to all nonattendees may yield a stronger effect on participation.