The identification of human papillomavirus (HPV) as the aetiological agent for cervical cancer has important implications for the future of cervical cancer screening and prevention strategies. Despite the availability of HPV vaccines, regular and adequate screening will remain the mainstay of cervical cancer screening for some time to come. Molecular tests for high-risk HPV DNA and E6/E7 mRNA have the potential to improve cervical cancer screening in developed and developing countries. The latest international and South African private sector guidelines propose the incorporation of molecular testing for HPV in screening and patient management, backed by good scientific evidence. It is a time of transition for screening programmes; a move from the annual Pap test to a new viral paradigm. This review discusses the proper placement, advantages and disadvantages of cytology versus HPV-based screening tests from a South African perspective.