Despite the implementation of various screening programs in many countries, cervical cancer continues to be a major health problem. Cervical cytology is the most used screening method, but human papillomavirus (HPV) genotyping, alone or in combination with cytology, has gained ground during the last years. Still, one of the major limitations of HPV-genotyping is the low specificity of HPV as a screening method in young women that are HPV-positive, but with no potential for future disease. Obviously, there is a need for a better screening algorithm. The ideal screening test for cervical high-grade lesions should detect the effect of high-risk (HR)-HPV infection after cell transformation, but not before, and should accurately identify the cases that are more likely to experience disease progression to neoplasia. Solid data regarding the benefit of immunocytochemistry in the evaluation of the patients with modified cervical cytology have been published recently. The use of the dual staining with p16INK4a and Ki-67 could increase specificity of the method for the detection of atypical cells and may perform better in predicting the risk of high-grade dysplasia in the near future.